4-oxy-N-[1,3,4]-thiadiazol-2-yl-benzene sulfonamides, pharmaceutical compositions and methods for their therapeutic use

ABSTRACT

The present invention comprises 4-Oxy-N-[1,3,4]-thiadiazol-2-yl-benzene sulfonamides, the derivatives thereof and salts thereof as well as processes for their preparation and methods for their use as pharmaceutical compositions. More specifically, the invention relates to 4-oxy-N-[1,3,4]-thiadiazol-2-yl-benzene sulfonamides and to their physiologically acceptable salts and physiologically functional derivatives that exhibit peroxisome proliferator activator receptor (PPAR) PPARalpha, PPARdelta and PPARgamma agonist activity. The compounds themselves are defined by the structure of the formula I, 
                         
wherein the various unnamed substituents are defined herein. The compounds are suitable for the treatment of disorders of fatty acid metabolism and glucose utilization disorders as well as of disorders in which insulin resistance is involved as well as demyelinating and other neurodegenerative disorders of the central and peripheral nervous system.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Patent ApplicationNo. PCT/EP2006/009297 filed on Sep. 26, 2006 which is incorporatedherein by reference in its entirety which also claims the benefit ofpriority of European Patent Application No. 05021786.0 filed on Oct. 6,2005.

FIELD OF THE INVENTION

The present invention relates generally to pharmaceutical compositionsfor the treatment of metabolic disorders and the diseases andphysiological problems resulting there from. More specifically, thepresent invention relates to compounds which are able to therapeuticallymodulate lipid and/or carbohydrate metabolism in mammals and are thussuitable for the prevention and/or treatment of diseases such as type-2diabetes, atherosclerosis, cardiovascular disorders and the like. Theinventive compounds of the present invention are also useful in thetreatment of the demyelinating and other neurodegenerative disorders ofthe central and peripheral nervous systems.

BACKGROUND OF THE INVENTION

Peroxisome proliferator activated receptor (PPAR) agonists are wellknown and have been described in the prior art, (see U.S. Pat. No.6,200,995 to De La Brouse-Elwood et. al.; WO 03/043997 to Johnston et.al. and WO 01/00603 and WO 02/092590 to Keil et. al.) Benzenesulfonaminocompounds which bind to PPARs are described in WO 2005/005421.Sulfonamide compounds comprising showing hypoglycemic activity aredisclosed in Khimiko-Farmatsevticheskii Zhurnal (1987), 21(8), 965-8.From WO 97/40017 compounds having a phenyl group linked to heterocyclicring compounds are known as modulators of molecules with phosphotyrosinerecognition units.

The present invention comprises pharmaceutical compounds andcompositions that therapeutically modulate lipid and/or carbohydratemetabolism and are thus suitable for the prevention and/or treatment ofdiseases such as type-2 diabetes, atherosclerosis and the physiologicalmanifestations thereof. These compounds are also therapeuticallyeffective in the treatment of demyelinating and other neurodegenerativedisorders of the central and peripheral nervous systems. Morespecifically, the compounds of the present invention modulate theactivity of peroxisome proliferator activated receptors (PPAR). Thecompounds are suitable in particular for activating PPARdelta orPPARdelta and PPARgamma receptors, however, the relative activation ofeach respective compound varies depending on the specific compoundadministered.

Peroxisome proliferator-activated receptors (PPAR) are transcriptionfactors which can be activated by ligands and belong to the class ofnuclear hormone receptors. There are three PPAR isoforms, PPARalpha,PPARgamma and PPARdelta (identical to PPARbeta), which are encoded bydifferent genes (Peroxisome proliferator-activated receptor (PPAR):structure, mechanisms of activation and diverse functions: Motojima K.,Cell Struct Funct., 1993, 18(5), 267-77).

In humans, PPARgamma exists in three variants, PPARgamma₁, gamma₂, andgamma₃, which are the result of alternative use of promoters anddifferential mRNA splicing. Different PPARs have different tissuedistribution and modulate different physiological functions. The PPARsplay a key role in various aspects of the regulation of a large numberof genes, the products of which genes are directly or indirectlycrucially involved in lipid and carbohydrate metabolism. Thus, forexample, the PPARalpha receptor plays an important part in theregulation of fatty acid catabolism or lipoprotein metabolism in theliver, while PPARgamma is crucially involved for example in regulatingadipose cell differentiation. In addition, however, PPARs are alsoinvolved in the regulation of many other physiological processes,including those which are not directly connected with carbohydrate orlipid metabolism. The activity of different PPARs can be modulated byvarious fatty acids, fatty acid derivatives and synthetic compounds tovarying extents. For relevant reviews about functions, physiologicaleffects and pathophysiology, see: Berger, J. et al., Annu. Rev. Med.,2002, 53, 409-435; Wilson, T. et al., J. Med. Chem., 2000, 43 (4),527-550; Kliewer, S. et al., Recent Prog Horm Res., 2001, 56, 239-63;Moller, D. E. and Berger, J. P., Int J Obes Relat Metab Disord., 2003,27 Suppl 3, 17-21; Ram, V. J., Drugs Today, 2003, 39(8), 609-32).

Among the three PPAR-isoforms the physiological functions of PPARdeltahave long remained an enigma. The first proposed pharmacological rolefor PPARdelta has been the regulation of cholesterol homeostasis. It wasshown that the somewhat selective PPARdelta ligand L-165041 raisesplasma cholesterol in a diabetic animal model (Berger J. et al., J.Biol. Chem., 1999, 274, 6718-6725; Leibowitz M. D. et al., FEBS Lett.,2000, 473(3), 333-336). In obese, insulin resistant rhesus monkeys, thepotent and selective PPARdelta ligand GW501516 raises HDL-cholesterol,decreases plasma LDL-cholesterol, triglycerides and insulin levels(Oliver, W. et al., Proc. Natl. Acad. Sci., 2001, 98, 5306-5311). Thedual PPARdelta/PPARalpha agonist YM-16638 significantly lowers plasmalipids in rhesus and cynomolgus monkeys (Goto, S. et al., Br. J. Pharm.,1996, 118, 174-178) and acts in a similar manner in two weeks clinicaltrials in healthy volunteers (Shimokawa, T. et al., Drug Dev. Res.,1996, 38, 86-92). More recent publications underline that PPARdelta isan important target for the treatment of dyslipidemia, insulinresistance, type 2 diabetes, atherosclerosis and syndrome X (Wang, Y-X.et al., Cell, 2003, 113, 159-170; Luquet, S. et al., FASEB J., 2003, 17,209-226; Tanaka, T. et al., PNAS, 2003, 100, 15924-15929; Holst, D. etal., BioChem. Biophys. Acta, 2003, 1633, 43-50; Dressel, U. et al., Mol.Endocrin., 2003, 17, 2477-2493; Lee, C. H. et al., Science, 2003, 302,453-457).

Besides its actions as a regulator of the lipid-, glucose- andcholesterol-metabolism PPARdelta is known to play a role in embryonicdevelopment, implantation and bone formation (Lim, H. and Dey, S. K.,Trends Endocrinol Metab., 2000, 11(4), 137-42; Ding, N. Z. et al., MolReprod Dev., 2003, 66(3), 218-24; Mano, H. et al., J Biol. Chem., 2000,275(11), 8126-32).

Numerous publications demonstrate that PPARdelta is triggeringproliferation and differentiation of keratinocytes which points to itsrole in skin disorders and wound healing (Di-Poi, N. et al., J SteroidBiochem Mol. Biol., 2003, 85(2-5), 257-65; Tan, N. S. et al., Am J ClinDermatol., 2003, 4(8), 523-30; Wahli, W., Swiss Med. Wkly., 2002,132(7-8), 83-91).

PPARdelta appears to be significantly expressed in the CNS; however muchof its function there still remains undiscovered. Of singular interesthowever, is the discovery that PPARdelta was expressed in rodentoligodendrocytes, the major lipid producing cells of the CNS (J.Granneman, et al., J. Neurosci. Res., 1998, 51, 563-573). Moreover, itwas also found that a PPARdelta selective agonist was found tosignificantly increase oligodendro-glial myelin gene expression andmyelin sheath diameter in mouse cultures (I. Saluja et al., Glia, 2001,33, 194-204). Thus, PPARdelta activators may be of use for the treatmentof demyelinating and dysmyelinating diseases. The use of peroxisomeproliferator activated receptor delta agonists for the treatment of MSand other demyelinating diseases can be shown as described inWO2005/097098.

Demyelinating conditions are manifested in loss of myelin—the multipledense layers of lipids and protein which cover many nerve fibers. Theselayers are provided by oligodendroglia in the central nervous system(CNS), and Schwann cells in the peripheral nervous system (PNS). Inpatients with demyelinating conditions, demyelination may beirreversible; it is usually accompanied or followed by axonaldegeneration, and often by cellular degeneration. Demyelination canoccur as a result of neuronal damage or damage to the myelinitself—whether due to aberrant immune responses, local injury, ischemia,metabolic disorders, toxic agents, or viral infections (Prineas andMcDonald, Demyelinating Diseases. In Greenfield's Neuropathology,6.sup.th ed. (Edward Arnold: New York, 1997) 813-811, Beers and Berkow,eds., The Merck Manual of Diagnosis and Therapy, 17.sup.th ed.(Whitehouse Station, N.J.: Merck Research Laboratories, 1999) 1299,1437, 1473-76, 1483).

Central demyelination (demyelination of the CNS) occurs in severalconditions, often of uncertain etiology, that have come to be known asthe primary demyelinating diseases. Of these, multiple sclerosis (MS) isthe most prevalent. Other primary demyelinating diseases includeadrenoleukodystrophy (ALD), adrenomyeloneuropathy, AIDS-vacuolarmyelopathy, HTLV-associated myelopathy, Leber's hereditary opticatrophy, progressive multifocal leukoencephalopathy (PML), subacutesclerosing panencephalitis, Guillian-Barre syndrome and tropical spasticparaparesis. In addition, there are acute conditions in whichdemyelination can occur in the CNS, e.g., acute disseminatedencephalomyelitis (ADEM) and acute viral encephalitis. Furthermore,acute transverse myelitis, a syndrome in which an acute spinal cordtransaction of unknown cause affects both gray and white matter in oneor more adjacent thoracic segments, can also result in demyelination.Also, disorders in which myelin forming glial cells are damagedincluding spinal cord injuries, neuropathies and nerve injury.

Benzenesulfonamino compounds which bind to PPARs are described in WO2005/005421. From WO 97/40017 compounds having a phenyl group linked toheterocycles are known as modulators of molecules with phosphotyrosinerecognition units. Arylcarbonyl derivatives which are activators ofglucokinase are described in WO 2004/002481.

The present invention is based on the discovery of a group of novelcompounds which are effectively modulate lipid and/or carbohydratemetabolism and are thus suitable in the treatment of diseases such astype-2 diabetes and atherosclerosis and the physical manifestationsthereof as well as the treatment of demyelinating and otherneurodegenerative disorders of the central and peripheral nervoussystems. More specifically, these compounds are effective in this waythrough the modulation of the activity of peroxisomeproliferator-activated receptors (PPAR) receptors, in particular foractivating PPARalpha, PPARdelta and PPARgamma receptors. One must bearin mind however, that it is possible that the relative activation variesdepending on the specific compounds administered.

Peroxisome proliferator-activated receptors (PPAR) are transcriptionfactors which can be activated by ligands and belong to the class ofnuclear hormone receptors. There are three PPAR isoforms, PPARalpha,PPARgamma and PPARdelta (identical to PPARbeta), which are encoded bydifferent genes (Peroxisome proliferator-activated receptor (PPAR):structure, mechanisms of activation and diverse functions: Motojima K.,Cell Struct Funct., 1993, 18(5), 267-77).

SUMMARY OF THE INVENTION

The present invention relates to 4-oxy-N-[1,3,4]-thiadiazol-2-yl-benzenesulfonamides and to their physiologically acceptable salts andphysiologically functional derivatives showing PPARdelta and PPAR gammaagonist activity. Compounds of the present invention are described byformula I:

wherein

-   R1 is selected from the group consisting of (C1-C6) alkyl, (C0-C6)    alkylene-(C3-C6) cycloalkyl, (C0-C6) alkylene-O—(C1-C6) alkyl,    (C0-C6) alkylene-O—(C3-C6) cycloalkyl, (C0-C6) alkylene-(C6-C14)    aryl and (C0-C6) alkylene-(C5-C15) heteroaryl, wherein alkyl,    alkylene, aryl and cycloalkyl are unsubstituted or mono-, di- or    trisubstituted by F, Cl, Br, (C1-C6) alkyl, O—(C1-C6) alkyl, CF₃,    OCF₃, CN, CO—(C1-C6) alkyl, COO—(C1-C6) alkyl, CON((C0-C6)    alkylene-H) (C0-C6) alkylene-H), S(O)_(m)(C1-C6) alkyl;-   R2 and R3 are independently selected from the group consisting of H,    halogen, (C1-C6) alkyl, (C0-C4) alkylene-O—(C0-C4) alkylene-H, SCH3,    CN, wherein alkyl and alkylene is unsubstituted or mono-, di- or    trisubstituted by F;-   R4, R5, R6 and R7 are independently selected from the group    consisting of H, (C1-C6) alkyl, (C0-C4) alkylene-(C3-C6) cycloalkyl,    (C0-C6) alkylene-(C6-C14) aryl, (C0-C6) alkylene-(C5-C15)    heteroaryl, (C0-C6) alkylene-(C3-C15) heterocycloalkyl and (C0-C6)    alkylene-(C3-C15) heterocycloalkenyl, wherein alkyl, cycloalkyl,    aryl, heterocycloalkyl, heterocycloalkenyl and heteroaryl are    unsubstituted or mono-, di- or trisubstituted by F, Cl, Br, CF3,    (C1-C4) alkyl and (C0-C4)-alkylene-O—(C0-C4) alkylene-H;-   m is 0 and 1;-   A is selected from the group consisting of, (C6-C14) aryl and    (C5-C15) heteroaryl;-   B is selected from the group consisting of, (C6-C14) aryl, (C3-C12)    cycloalkyl, (C5-C15) heteroaryl;-   Z is a bond, O or-   Ring A and Ring B are joined together to form an annealed (C5-C15)    heterocyclic or (C8-C14) aromatic ring system; and Z is absent-   R8, R9 are independently selected from the group consisting of H,    halogen, (C1-C6) alkyl, (C0-C4) alkylene-O—(C0-C4) alkylene-H, SCF3,    SF5, S(O)2CF3, O—(C6-C14) aryl, (C6-C14) aryl and NO2, wherein alkyl    and alkylene is unsubstituted or mono, bi- or trisubstituted by F    and wherein aryl is unsubstituted or mono-, di- or trisubstituted by    F, Cl, Br, CF3, (C1-C4) alkyl and (C0-C4)-alkylene-O—(C0-C4)    alkylene-H;-   p is 0, 1, 2 or 3;-   q is 0, 1 or 2;    its' stereoisomers, enantiomers, tautomers, their physiologically    acceptable salts and mixtures thereof.

A second embodiment of the present invention is compounds of the formulaI wherein one or more substituents have the following meaning:

-   R1 is selected from the group consisting of (C1-C6) alkyl, (C0-C6)    alkylene-O—(C1-C6) alkyl and (C0-C6) alkylene-(C6-C14) aryl, wherein    alkyl, alkylene and aryl are unsubstituted or mono- or disubstituted    by F;-   R2 and R3 are independently H, halogen, (C1-C6) alkyl, (C0-C4)    alkylene-O—(C0-C4) alkylene-H, wherein alkyl and alkylene is    unsubstituted or mono-, di- or trisubstituted by F;-   R4, R5, R6 and R7 are such that one of the four substituents is    selected from the group consisting of H, (C1-C6) alkyl, (C0-C2)    alkylene-(C3-C6) cycloalkyl, (C0-C2) alkylene-(C6-C10) aryl, (C0-C2)    alkylene-(C5-C10) heteroaryl, (C0-C2) alkylene-(C3-C10)    heterocycloalkyl, (C0-C2) alkylene-(C3-C10) heterocycloalkenyl,    wherein alkyl, cycloalkyl, aryl, heterocycloalkyl,    heterocycloalkenyl and heteroaryl are unsubstituted or mono-, di- or    trisubstituted by F, Cl, CF3, (C1-C4) alkyl and    (C0-C4)-alkylene-O—(C0-C4) alkylene-H;    and the other three substituents is H-   m is 0, 1;-   A is (C6-C10) aryl, (C5-C10) heteroaryl;-   B is (C6-C10) aryl, (C6-C8) cycloalkyl, (C5-C10) heteroaryl;-   Z is a bond or O;-   A and B together form an annealed (C8-C10) heterocyclic ring and Z    is absent-   Z is absent;-   R8 is H, (C1-C6) alkyl;-   R9 is selected from the group consisting of H, (C1-C6) alkyl,    (C0-C4) alkylene-O—(C0-C4) alkylene-H, and O—(C6-C10) aryl, wherein    alkyl and alkylene is unsubstituted or mono, bi- or trisubstituted    by F;-   p is 0, 1, 2;-   q is 0, 1.

Another embodiment according to the invention are compounds of theformula I wherein

-   R1 is (C1-C6) alkyl, phenyl, (C3-C6) cycloalkyl.

Yet another embodiment according to the invention are compounds of theformula I wherein

-   R1 is isopropyl.

Another embodiment according to the invention are compounds of theformula I wherein

-   R2 and R3 are H.

Another embodiment according to the invention are compounds of theformula I wherein

-   R4, R5, R6 and R7 are H.

Another embodiment according to the invention are compounds of theformula I wherein

-   m is 0.

Another embodiment according to the invention are compounds of theformula I wherein

-   A is oxazole, thiazole, phenyl, 1,2,4-oxadiazole.

Another embodiment according to the invention are compounds of theformula I wherein

-   B is phenyl or cyclohexyl.

Another embodiment according to the invention is compounds of theformula I wherein

-   Z is a bond.

Another embodiment according to the invention are compounds of theformula I wherein A and B together form a benzo-furan ring and Z isabsent.

Another embodiment according to the invention are compounds of theformula I wherein

-   R8 is selected from the group consisting of H, (C1-C4) alkyl and-   p is 0 or 1.

Another embodiment according to the invention are compounds of theformula I wherein

-   R9 is H, CF3, O—(C1-C4) alkyl, phenoxy and-   q is 1.

More specific embodiments of the present invention are the compounds:

-   N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzenesulfonamide-   N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[4-methyl-2-(3-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzenesulfonamide-   N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-(6-methoxy-benzofuran-3-ylmethoxy)-benzenesulfonamide-   N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[4-(4-trifluoromethyl-phenoxy)-benzyloxy]-benzenesulfonamide-   N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[4-(2-methoxy-phenoxy)-benzyloxy]-benzenesulfonamide-   4-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-benzenesulfonamide-   N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[5-methyl-2-(4-phenoxy-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonamide-   4-(2-Cyclohexyl-oxazol-4-ylmethoxy)-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-benzenesulfonamide-   N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[5-(4-methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethoxy]-benzenesulfonamide-   N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzenesulfonamide-   4-(2-Biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-benzenesulfonamide-   N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-(5-methoxy-benzofuran-2-ylmethoxy)-benzenesulfonamide-   N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[2-(4-methoxy-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonamide-   4-[5-Ethyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-benzenesulfonamide-   N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[5-methyl-2-(4-trifluoromethoxy-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonamide-   N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[5-isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonamide-   4-[5-Ethyl-2-(2-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-benzenesulfonamide-   4-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-N-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-benzenesulfonamide-   N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy}-benzenesulfonamide

This invention also encompasses all combinations of preferred aspects ofthe invention described herein.

As used herein, the term “alkyl” is to be understood in the broadestsense to mean saturated hydrocarbon residues which can be linear, i.e.straight-chain, or branched. If not otherwise defined alkyl has 1 to 8carbon atoms. Examples of “—(C1-C8)-alkyl” are alkyl residues containing1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms are methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl or octyl, the n-isomers of all these residues,isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl,2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, sec-butyl,tert-butyl or tert-pentyl. The term “—(C0-C8)-alkyl” is a hydrocarbonresidue containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, in which theterm “—C0-alkyl” is a covalent bond. All these statements apply also tothe term alkylene.

As used herein, the term “alkenyl” is to be understood in the broadestsense to mean hydrocarbon residues which has 1 to 4 double bonds and canbe linear, i.e. straight-chain, or branched. If not otherwise definedalkenyl has 2 to 8 carbon atoms. Examples of “—(C2-C8)-alkenyl” arealkenyl residues containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms are, forexample vinyl, 1-propenyl, 2-propenyl (=allyl), 2-butenyl, 3-butenyl,2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl or 1,3-pentadienyl.All these statements apply also to the term alkenylene.

As used herein, the term “alkynyl” is to be understood in the broadestsense to mean hydrocarbon residues, which has 1 to 4 triple bonds andcan be linear, i.e. straight-chain, or branched. If not otherwisedefined alkynyl has 2 to 8 carbon atoms. Examples of “—(C2-C8)-alkynyl”are alkynyl residues containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms are,for example ethynyl, 1-propynyl, 2-propynyl (=propargyl) or 2-butynyl.All these statements apply also to the term alkylidene.

All these statements also apply if an alkyl group occurs as asubstituent on another residue, for example in an alkyloxy residue, analkyloxycarbonyl residue or an arylalkyl residue.

If not otherwise defined, alkyl, alkylene, alkenyl, alkenylene, alkynyland alkynylene are unsubstituted or mono, di- or trisubstitutedindependently of one another by suitable groups such as, for example: F,Cl, Br, I, CF3, NO2, CN, COOH, CO—O—(C0-C4) alkylene-(C6-C10) aryl,CO—O—(C1-C4) alkyl, CO—O—(C0-C4) alkylene-(C3-C13)cycloalkyl,CO—O—(C0-C4) alkylene-(C3-C15)heterocycle, CO—N((C0-C4)alkylene-H)—(C0-C4) alkylene-(C6-C10) aryl, CO—N((C0-C4)alkylene-H)—(C0-C4) alkylene-H, CO—N((C0-C4) alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl, CO—N((C0-C4) alkylene-H)—(C0-C4)alkylene-(C3-C15) heterocycle, (C0-C4) alkylene-(C3-C6)cycloalkyl,(C0-C4) alkylene-(C6-C10)aryl, (C0-C4) alkylene-(C3-C15)heterocycle,(C2-C6)-alkenyl, (C2-C6)-alkynyl, O—(C0-C6)-alkyl, O—(C0-C4)alkylene-(C6-C10) aryl, O—(C0-C4) alkylene-(C3-C12)cycloalkyl, O—(C0-C4)alkylene-(C3-C15)heterocycle, O—CO—O—(C0-C4) alkylene-(C6-C10) aryl,O—CO—O—(C1-C4) alkyl, O—CO—O—(C0-C4) alkylene-(C3-C13)cycloalkyl,O—CO—O—(C0-C4) alkylene-(C3-C15)heterocycle, S—(C1-C4)alkyl, S—(C0-C4)alkylene-(C3-C13)cycloalkyl, S—(C0-C4) alkylene-(C6-C10) aryl, S—(C0-C4)alkylene-(C3-C15) heterocycle, SO—(C1-C4)alkyl, SO—(C0-C4)alkylene-(C3-C13)cycloalkyl, SO—(C0-C4) alkylene-(C6-C10) aryl,SO—(C0-C4) alkylene-(C3-C15) heterocycle, SO2-(C1-C4)alkyl, SO2-(C0-C4)alkylene-(C3-C13)cycloalkyl, SO2-(C0-C4) alkylene-(C6-C10) aryl,SO2-(C0-C4) alkylene-(C3-C15) heterocycle,SO2-N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C6-C10)aryl,SO2-N((C0-C4)alkylene-H)—(C0-C4)alkylene-H, SO2-N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl,SO2-N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle where thearyl ring or heterocyclic ring is unsubstituted or mono- ordisubstituted by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl,(C1-C6)-alkyl, N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H;N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H, N((C0-C4)alkylene-H)—(C0-C4)alkylene-H)—(C1-C6)cycloalkyl,N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle,where the aryl ring or heterocyclic ring is unsubstituted or mono- ordisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl,(C1-C6)-alkyl, N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H, SO2-CH3, COOH,COO—(C1-C6)-alkyl, SF5, CONH2.

The term cycloalkyl is to be understood to mean saturated hydrocarboncycle containing from 3 to 13 carbon atoms in a mono- or bicyclic,fused, bridged or spirocyclic ring. Examples of (C3-C13)-cycloalkylcyclic alkyl residues are cycloalkyl residues containing 3, 4, 5, 6, 7,8, 9, 10, 11, 12 or 13 ring carbon atoms like cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, cycloundecyl or cyclododecyl. The term cycloalkyl alsoincludes bicyclic groups in which any of the above cycloalkyl ring isfused to a benzene ring, for example indane and1,2,3,4-tetrahydronaphthalene.

The term cycloalkenyl is to be understood to mean unsaturatedhydrocarbon cycle containing from 3 to 8 carbon atoms in a mono- orbicyclic, fused or bridged ring, wherein the one, two or three doublebonds are not located within a cyclic alkyl group in such a manner thatan aromatic system results. Examples of unsaturated cycloalkenyl groupsare cyclopentenyl or cyclohexenyl, which can be bonded via any carbonatom. The term cycloalkenyl also includes bicyclic groups in which anyof the above cycloalkenyl ring is fused to a benzene ring, for example1,2-dihydronaphthalene, 1,4-dihydronaphthalene and 1H-indene.

If not otherwise defined cycloalkyl or cycloalkenyl are unsubstituted ormono-, di- or trisubstituted independently of one another by suitablegroups such as, for example: F, Cl, Br, I, CF3, NO2, CN, COOH,CO—O—(C0-C4) alkylene-(C6-C10) aryl, CO—O—(C1-C4) alkyl, CO—O—(C0-C4)alkylene-(C3-C13)cycloalkyl, CO—O—(C0-C4) alkylene-(C3-C15)heterocycle,CO—N((C0-C4) alkylene-H)—(C1-C6)alkylene-H, CO—N((C0-C4)alkylene-H)—(C1-C6)cycloalkyl, CON((C0-C4)alkylene-H)—(C0-C4)alkylene-(C6-C12)-aryl, (C0-C4)alkylene-(C3-C6)cycloalkyl, (C3-C6)alkyl, (C2-C6)-alkenyl,(C2-C6)-alkynyl, (C0-C4) alkylene-(C6-C10)aryl, (C0-C4)alkylene-(C3-C15)heterocycle, O—(C0-C6)-alkyl, (C0-C4)alkylene-O—(C0-C4) alkyl, (C0-C4) alkylene-O—(C0-C4)alkylene-(C3-C13)cycloalkyl, (C0-C4) alkylene-O—(C0-C4)alkylene-(C6-C10)aryl, (C0-C4) alkylene-O—(C0-C4)alkylene-(C3-C15)heterocycle, O—CO—O—(C0-C4) alkylene-(C6-C10) aryl,O—CO—O—(C1-C4) alkyl, O—CO—O—(C0-C4) alkylene-(C3-C13)cycloalkyl,O—CO—O—(C0-C4) alkylene-(C3-C15)heterocycle, O—CO—N((C0-C4)alkylene-H)—(C0-C4) alkylene-(C6-C10) aryl, O—CO—N((C0-C4)alkylene-H)—(C0-C4) alkylene-H, O—CO—N((C0-C4) alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl, O—CO—N((C0-C4) alkylene-H)—(C0-C4)alkylene-(C3-C15) heterocycle, S—(C1-C4)alkyl, S—(C0-C4)alkylene-(C3-C13)cycloalkyl, S—(C0-C4) alkylene-(C6-C10) aryl, S—(C0-C4)alkylene-(C3-C15) heterocycle, SO—(C1-C4)alkyl, SO—(C0-C4)alkylene-(C3-C13)cycloalkyl, SO—(C0-C4) alkylene-(C6-C10) aryl,SO—(C0-C4) alkylene-(C3-C15) heterocycle, SO2-(C1-C4)alkyl, SO2-(C0-C4)alkylene-(C3-C13)cycloalkyl, SO2-(C0-C4) alkylene-(C6-C10) aryl,SO2-(C0-C4) alkylene-(C3-C15) heterocycle,SO2-N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C6-C10)aryl,SO2-N((C0-C4)alkylene-H)—(C0-C4)alkylene-H, SO2-N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl,SO2-N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle, where thearyl ring or heterocyclic ring is unsubstituted or mono- ordisubstituted by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl,(C1-C6)-alkyl, N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H;N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H, N((C0-C4)alkylene-H)—(C0-C4)alkylene-H)—(C1-C6)cycloalkyl,N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle,where the aryl or heterocyclic ring is unsubstituted or mono- ordisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl,(C1-C6)-alkyl, N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H, SO2-CH3, COOH,COO—(C1-C6)-alkyl, SF5, CONH2.

The term “aryl” is understood to mean aromatic hydrocarbon ringcontaining from 6 to 14 carbon atoms in a mono- or bicyclic ring.Examples of (C6-C14)-aryl rings are phenyl, naphthyl, for example1-naphthyl and 2-naphthyl, biphenyl, for example 2-biphenyl, 3-biphenyland 4-biphenyl, anthryl or fluorenyl. Biphenyl rings, naphthyl ring and,in particular, phenyl ring are further embodiments of aryl ring.

The terms “heterocycle” is understood to mean saturated(heterocycloalkyl), partly unsaturated (heterocycloalkenyl) orunsaturated (heteroaryl)hydrocarbon rings containing from 3 to 15 carbonatoms in a mono- or bicyclic, fused, bridged or spirocyclic ring inwhich 1 to 5 carbon atoms of the 3 to 15 ring carbon atoms are replacedby heteroatoms such as nitrogen, oxygen or sulfur in which further theheteroatoms can be oxidized, for example N═O, S═O, SO2. Examples ofheterocyclic ring compounds are acridinyl, azaindole(1H-pyrrolopyridinyl), azabenzimidazolyl, azaspirodecanyl, azepinyl,azetidinyl, aziridinyl, benzimidazolyl, benzofuranyl,dihydrobenzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydrochinolinyl, 4,5-dihydrooxazolinyl,dioxazolyl, dioxazinyl, 1,3-dioxolanyl, 1,3-dioxolenyl,3,3-dioxo[1,3,4]oxathiazinyl, 6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]-tetrahydrofuranyl, furanyl, furazanyl,imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl(benzimidazolyl),isothiazolyl, isothiazolidinyl, isothiazolinyl, isoxazolyl,isoxazolinyl, isoxazolidinyl, 2-isoxazolinyl, ketopiperazinyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,2-oxa-thiepanyl, 1,2-oxathiolanyl, 1,4-oxazepanyl,1,4-oxazepinyl, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl,oxazolinyl, oxazolyl, oxetanyl, oxocanyl, phenanthridinyl,phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl,phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinonyl,pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothiophenyl,tetrazinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, 1,2-thiazinyl, 1,3-thiazinyl, 1,4-thiazinyl,1,3-thiazolyl, thiazolyl, thiazolidinyl, thiazolinyl, thienyl,thietanyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,thiomorpholinyl, thiophenolyl, thiophenyl, thiopyranyl, 1,2,3-triazinyl,1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.

The heterocyclic rings are unsubstituted or mono-, di- or trisubstitutedby suitable groups such as, for example: F, Cl, Br, I, CF3, NO2, CN,COOH, CO—O—(C0-C4) alkylene-(C6-C10) aryl, CO—O—(C1-C4) alkyl,CO—O—(C0-C4) alkylene-(C3-C13)cycloalkyl, CO—O—(C0-C4)alkylene-(C3-C15)heterocycle, CO—N((C0-C4)alkylene-H)—(C1-C6)alkylene-H, CO—N((C0-C4)alkylene-H)—(C1-C6)cycloalkyl, CON((C0-C4)alkylene-H)—(C0-C4)alkylene-(C6-C12)-aryl, (C0-C4)alkylene-(C3-C6)cycloalkyl, (C3-C6)alkyl, (C2-C6)-alkenyl,(C2-C6)-alkynyl, (C0-C4) alkylene-(C6-C10)aryl, (C0-C4)alkylene-(C3-C15)heterocycle, O—(C0-C6)-alkyl, (C0-C4)alkylene-O—(C0-C4) alkyl, (C0-C4) alkylene-O—(C0-C4)alkylene-(C3-C13)cycloalkyl, (C0-C4) alkylene-O—(C0-C4)alkylene-(C6-C10)aryl, (C0-C4) alkylene-O—(C0-C4)alkylene-(C3-C15)heterocycle, O—CO—O—(C0-C4) alkylene-(C6-C10) aryl,O—CO—O—(C1-C4) alkyl, O—CO—O—(C0-C4) alkylene-(C3-C13)cycloalkyl,O—CO—O—(C0-C4) alkylene-(C3-C15)heterocycle, O—CO—N((C0-C4)alkylene-H)—(C0-C4) alkylene-(C6-C10) aryl, O—CO—N((C0-C4)alkylene-H)—(C0-C4) alkylene-H, O—CO—N((C0-C4) alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl, O—CO—N((C0-C4) alkylene-H)—(C0-C4)alkylene-(C3-C15) heterocycle, S—(C1-C4)alkyl, S—(C0-C4)alkylene-(C3-C13)cycloalkyl, S—(C0-C4) alkylene-(C6-C10) aryl, S—(C0-C4)alkylene-(C3-C15) heterocycle, SO—(C1-C4)alkyl, SO—(C0-C4)alkylene-(C3-C13)cycloalkyl, SO—(C0-C4) alkylene-(C6-C10) aryl,SO—(C0-C4) alkylene-(C3-C15) heterocycle, SO2-(C1-C4)alkyl, SO2-(C0-C4)alkylene-(C3-C13)cycloalkyl, SO2-(C0-C4) alkylene-(C6-C10) aryl,SO2-(C0-C4) alkylene-(C3-C15) heterocycle,SO2-N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C6-C10)aryl,SO2-N((C0-C4)alkylene-H)—(C0-C4)alkylene-H, SO2-N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl,SO2-N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle, where thearyl ring or heterocyclic ring is unsubstituted or mono- ordisubstituted by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl,(C1-C6)-alkyl, N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H;

N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H, N((C0-C4)alkylene-H)—(C0-C4)alkylene-H)—(C1-C6)cycloalkyl,N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle,where the aryl or heterocyclic ring is unsubstituted or mono- ordisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl,(C1-C6)-alkyl, N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H, SO2-CH3, COOH,COO—(C1-C6)-alkyl, SF5, CONH2.

The term “R5 and R6 together with the nitrogen atom to which they arebonded (Y═N(R6)) can form a (C3-C9)-heterocycle which for example cancontain additionally 1 to 3 heteroatoms” refer to structures ofheterocycles which can be derived from compounds such as for examplepyrrolidine, morpholine, thiomorpholine, piperidine, piperazine,azetidine, 2,3-dihydro-1H-isoindole, piperazin-2-one, azetidine,isoindoline, 2,5-diazabicyclo[2.2.1]heptane, thiomorpholine 1-oxide,thiomorpholine 1,1-dioxide, piperidin-4-one, piperidin-3-one,homopiperidine, homopiperazine, homomorpholine,2,3,6,7-tetrahydro-(1H)-1,4-diazepin-5(4H)-one,

4-oxazolidine, azetidin-3-one, thiazolidine, thiazolidine 1-oxide,thiazolidine 1,1-dioxide, 4-imidazolidinone,5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine,1,4-diazabicyclo[4.3.0]nonane, 2-aza-5-oxabicyclo[2.2.1]heptane,2-oxa-5-azabicyclo[2.2.1]heptane, diazabicyclo[4.4.0]decane,4,5,6,7-tetrahydrothieno[3,2-c]pyridine,4,5,6,7-tetrahydro-1H-imidazol[4,5-c]-pyridine,4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine,3,8-diaza-bicyclo[3.2.1]octane, octahydro-pyrrolo[3,4-c]pyrrole,2,5-diazabicyclo[2.2.2]octane,4-spiro-[3-(N-methyl-2-pyrrolidinone)]-piperidine,2,8-diaza-spiro[5.5]undecane, 2,7-diaza-spiro[4.4]nonane,3,9-diaza-spiro[5.5]undecane, 2,8-diaza-spiro[4.5]decane,2,7-diaza-spiro[3.5]nonane, 2,9-diaza-spiro[5.5]undecane,2,7-diaza-spiro[4.5]decane, 1-oxa-4,9-diaza-spiro[5.5]undecane,1-oxa-4,8-diaza-spiro[5.5]undecane.

The term “oxo-residue” or “═O” refers to residues such as carbonyl(—C(O)—) or nitroso (—N═O).

Halogen is fluorine, chlorine, bromine or iodine.

Optically active carbon atoms present in the compounds of the formula Ican independently of each other have R configuration or S configuration.The compounds of the formula I can be present in the form of pureenantiomers or pure diastereomers or in the form of mixtures ofenantiomers and/or diastereomers, for example in the form of racemates.The present invention relates to pure enantiomers and mixtures ofenantiomers as well as to pure diastereomers and mixtures ofdiastereomers. The invention comprises mixtures of two or of more thantwo stereoisomers of the formula I and it comprises all ratios of thestereoisomers in the mixtures. In case the compounds of the formula Ican be present as E isomers or Z isomers (or cis isomers or transisomers) the invention relates both to pure E isomers and pure Z isomersand to E/Z mixtures in all ratios. The invention also comprises alltautomeric forms of the compounds of the formula I.

Diastereomers, including E/Z isomers, can be separated into theindividual isomers, for example, by chromatography. Racemates can beseparated into the two enantiomers by customary methods, for example bychromatography on chiral phases or by resolution, for example bycrystallization of diastereomeric salts obtained with optically activeacids or bases. Stereochemically uniform compounds of the formula I canalso be obtained by employing stereochemically uniform startingmaterials or by using stereoselective reactions.

The compounds of the formula I may exist in the form of their racemates,racemic mixtures, pure enantiomers, diastereomers and mixtures ofdiastereomers as well in their tautomeric forms. The present inventionencompasses all these isomeric and tautomeric forms of the compounds ofthe formula I. These isomeric forms can be obtained by known methodseven if not specifically described in some cases.

Pharmaceutically acceptable salts are, because their solubility in wateris greater than that of the initial or basic compounds, particularlysuitable for medical applications. These salts must have apharmaceutically acceptable anion or cation. Suitable pharmaceuticallyacceptable acid addition salts of the compounds of the invention aresalts of inorganic acids such as hydrochloric acid, hydrobromic,phosphoric, metaphosphoric, nitric and sulfuric acid, and of organicacids such as, for example, acetic acid, benzenesulfonic, benzoic,citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic,lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonicand tartaric acid. Suitable pharmaceutically acceptable basic salts areammonium salts, alkali metal salts (such as sodium and potassium salts),alkaline earth metal salts (such as magnesium and calcium salts), andsalts of trometamol (2-amino-2-hydroxymethyl-1,3-propanediol),diethanolamine, lysine or ethylenediamine.

Salts with a pharmaceutically unacceptable anion such as, for example,trifluoroacetate likewise belong within the framework of the inventionas useful intermediates for the preparation or purification ofpharmaceutically acceptable salts and/or for use in nontherapeutic, forexample in vitro, applications.

The term “physiologically functional derivative” used herein refers toany physiologically tolerated derivative of a compound of the formula Iof the invention, for example an ester, which on administration to amammal such as, for example, a human is able to form (directly orindirectly) a compound of the formula I or an active metabolite thereof.

Physiologically functional derivatives also include prodrugs of thecompounds of the invention, as described, for example, in H. Okada etal., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can bemetabolized in vivo to a compound of the invention. These prodrugs maythemselves be active or not.

The compounds of the invention may also exist in various polymorphousforms, for example as amorphous and crystalline polymorphous forms. Allpolymorphous forms of the compounds of the invention belong within theframework of the invention and are a further aspect of the invention.

All references to “compound(s) of formula I” hereinafter refer tocompound(s) of the formula I as described above, and their salts,solvates and physiologically functional derivatives as described herein.

Methods of Use

This invention relates further to methods for the use of compounds ofthe formula I and their pharmaceutical compositions as peroxisomeproliferator activator receptor (PPAR) ligands. The PPAR ligands of theinvention are effective in the modulation of PPAR activity, especiallythe activity of PPARdelta and PPARalpha. Depending on the modulationprofile, the compounds of the formula I are suitable for the treatment,control and prophylaxis of the indications described hereinafter, andfor a number of other pharmaceutical applications connected thereto(see, for example, Berger, J., et al., Annu. Rev. Med., 2002, 53,409-435; Wilson, T. et al., J. Med. Chem., 2000, 43(4), 527-550;Kliewer, S. et al., Recent Prog Horm Res., 2001, 56, 239-63; Fruchart,J. C. et al., 2001, Pharmacological Research, 44(5), 345-52; Kersten, S.et al., Nature, 2000, 405, 421-424; Torra, I. P. et al., Curr OpinLipidol, 2001, 12, 245-254).

Compounds of this type are particularly suitable for the treatmentand/or prevention of:

-   1.—Disorders of fatty acid metabolism and glucose utilization    disorders.    -   Disorders in which insulin resistance is involved-   2. Diabetes mellitus, especially type-2 diabetes, related disorders    and the physical manifestations thereof. Particular aspects in this    connection are:    -   hyperglycemia,    -   improvement in insulin resistance,    -   improvement in glucose tolerance,    -   protection of the pancreatic β-cells    -   prevention of macro- and microvascular disorders-   3. Dyslipidemias and their sequelae such as, for example,    atherosclerosis, coronary heart disease, cerebrovascular disorders    etc, especially those (but not restricted thereto) which are    characterized by one or more of the following factors:    -   high plasma triglyceride concentrations, high postprandial        plasma triglyceride concentrations,    -   low HDL cholesterol concentrations    -   low ApoA lipoprotein concentrations    -   high LDL cholesterol concentrations    -   small dense LDL cholesterol particles    -   high ApoB lipoprotein concentrations-   4. Various other conditions which may be associated with the    metabolic syndrome, such as:    -   obesity (excess weight), including central obesity    -   thromboses, hypercoagulable and prothrombotic states (arterial        and venous)    -   high blood pressure    -   heart failure such as, for example (but not restricted thereto),        following myocardial infarction, hypertensive heart disease or        cardiomyopathy-   5. Disorders or conditions in which inflammatory reactions are    involved:    -   atherosclerosis such as, for example (but not restricted        thereto), coronary sclerosis including angina pectoris or        myocardial infarction, stroke    -   vascular restenosis or reocclusion    -   chronic inflammatory bowel diseases such as, for example,        Crohn's disease and ulcerative colitis    -   asthma    -   lupus erythematosus (LE) or inflammatory rheumatic disorders        such as, for example, rheumatoid arthritis    -   other inflammatory states-   6. Disorders of cell cycle or cell differentiation processes:    -   adipose cell tumors    -   lipomatous carcinomas such as, for example, liposarcomas    -   solid tumors and neoplasms such as, for example (but not        restricted thereto), carcinomas of the gastrointestinal tract,        of the liver, of the biliary tract and of the pancreas,        endocrine tumors, carcinomas of the lungs, of the kidneys and        the urinary tract, of the genital tract, prostate carcinomas etc    -   acute and chronic myeloproliferative disorders and lymphomas    -   angiogenesis-   7. Demyelinating and other neurodegenerative disorders of the    central and peripheral nervous systems including:    -   Alzheimer's disease    -   multiple sclerosis    -   Parkinson's disease    -   adrenoleukodystrophy (ALD)    -   adrenomyeloneuropathy    -   AIDS-vacuolar myelopathy    -   HTLV-associated myelopathy    -   Leber's hereditary optic atrophy    -   progressive multifocal leukoencephalopathy (PML)    -   subacute sclerosing panencephalitis    -   Guillian-Barre syndrome    -   tropical spastic paraparesis    -   acute disseminated encephalomyelitis (ADEM)    -   acute viral encephalitis    -   acute transverse myelitis    -   spinal cord and brain trauma    -   Charcot-Marie-Tooth disease-   8. Skin disorders and/or disorders of wound healing processes:    -   erythemato-squamous dermatoses such as, for example, psoriasis    -   acne vulgaris    -   other skin disorders and dermatological conditions which are        modulated by PPAR    -   eczemas and neurodermitis    -   dermatitis such as, for example, seborrheic dermatitis or        photodermatitis    -   keratitis and keratoses such as, for example, seborrheic        keratoses, senile keratoses, actinic keratosis, photo-induced        keratoses or keratosis follicularis    -   keloids and keloid prophylaxis    -   warts, including condylomata or condylomata acuminata    -   human papilloma viral (HPV) infections such as, for example,        venereal papillomata, viral warts such as, for example,        molluscum contagiosum, leukoplakia    -   papular dermatoses such as, for example, Lichen planus    -   skin cancer such as, for example, basal-cell carcinomas,        melanomas or cutaneous T-cell lymphomas    -   localized benign epidermal tumors such as, for example,        keratoderma, epidermal naevi    -   chilblains    -   wound healing-   9. Other disorders    -   high blood pressure    -   pancreatitis    -   syndrome X    -   polycystic ovary syndrome (PCOS)    -   asthma    -   osteoarthritis    -   lupus erythematosus (LE) or inflammatory rheumatic disorders        such as, for example, rheumatoid arthritis    -   vasculitis    -   wasting (cachexia)    -   gout    -   ischemia/reperfusion syndrome    -   acute respiratory distress syndrome (ARDS)        Formulations

The amount of the compound of formula I necessary to achieve the desiredbiological effect depends on a number of factors such as the specificcompound chosen, the intended use, the mode of administration and theclinical condition of the patient. The daily dose is generally in therange from 0.001 mg to 100 mg (typically from 0.01 mg to 50 mg) per dayand per kilogram of bodyweight, for example 0.1-10 mg/kg/day. Anintravenous dose may be, for example, in the range from 0.001 mg to 1.0mg/kg, which can suitably be administered as infusion of 10 ng to 100 ngper kilogram and per minute. Suitable infusion solutions for thesepurposes may contain, for example, from 0.1 ng to 10 mg, typically from1 ng to 10 mg, per milliliter. Single doses may contain, for example,from 1 mg to 10 g of the active ingredient. Thus, ampules for injectionsmay contain, for example, from 1 mg to 100 mg, and single-doseformulations which can be administered orally, such as, for example,capsules or tablets, may contain, for example, from 0.05 to 1000 mg,typically from 0.5 to 600 mg. For the therapy of the abovementionedconditions, the compounds of formula I may be used as the compounditself, but they are preferably in the form of a pharmaceuticalcomposition with an acceptable carrier. The carrier must, of course, beacceptable in the sense that it is compatible with the other ingredientsof the composition and is not harmful for the patient's health. Thecarrier may be a solid or a liquid or both and is preferably formulatedwith the compound as a single dose, for example as a tablet, which maycontain from 0.05% to 95% by weight of the active ingredient. Otherpharmaceutically active substances may likewise be present, includingother compounds of formula I. The pharmaceutical compositions of theinvention can be produced by one of the known pharmaceutical methods,which essentially consist of mixing the ingredients withpharmacologically acceptable carriers and/or excipients.

Pharmaceutical compositions of the invention are those suitable fororal, rectal, topical, peroral (for example sublingual) and parenteral(for example subcutaneous, intramuscular, intradermal or intravenous)administration, although the most suitable mode of administrationdepends in each individual case on the nature and severity of thecondition to be treated and on the nature of the compound of formula Iused in each case. Coated formulations and coated slow-releaseformulations also belong within the framework of the invention.Preference is given to acid- and gastric juice-resistant formulations.Suitable coatings resistant to gastric juice comprise cellulose acetatephthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulosephthalate and anionic polymers of methacrylic acid and methylmethacrylate.

Suitable pharmaceutical preparations for oral administration may be inthe form of separate units such as, for example, capsules, cachets,suckable tablets or tablets, each of which contain a defined amount ofthe compound of formula I; as powders or granules, as solution orsuspension in an aqueous or nonaqueous liquid; or as an oil-in-water orwater-in-oil emulsion. These compositions may, as already mentioned, beprepared by any suitable pharmaceutical method which includes a step inwhich the active ingredient and the carrier (which may consist of one ormore additional ingredients) are brought into contact. The compositionsare generally produced by uniform and homogeneous mixing of the activeingredient with a liquid and/or finely divided solid carrier, afterwhich the product is shaped if necessary. Thus, for example, a tabletcan be produced by compressing or molding a powder or granules of thecompound, where appropriate with one or more additional ingredients.Compressed tablets can be produced by tableting the compound infree-flowing form such as, for example, a powder or granules, whereappropriate mixed with a binder, glidant, inert diluent and/or one (ormore) surface-active/dispersing agent(s) in a suitable machine. Moldedtablets can be produced by molding the compound, which is in powder formand is moistened with an inert liquid diluent, in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual)administration comprise suckable tablets which contain a compound offormula I with a flavoring, normally sucrose and gum arabic ortragacanth, and pastlles which comprise the compound in an inert basesuch as gelatin and glycerol or sucrose and gum arabic.

Pharmaceutical compositions suitable for parenteral administrationcomprise preferably sterile aqueous preparations of a compound offormula I, which are preferably isotonic with the blood of the intendedrecipient. These preparations are preferably administered intravenously,although administration may also take place by subcutaneous,intramuscular or intradermal injection. These preparations canpreferably be produced by mixing the compound with water and making theresulting solution sterile and isotonic with blood. Injectablecompositions of the invention generally contain from 0.1 to 5% by weightof the active compound.

Pharmaceutical compositions suitable for rectal administration arepreferably in the form of single-dose suppositories. These can beproduced by mixing a compound of the formula I with one or moreconventional solid carriers, for example cocoa butter, and shaping theresulting mixture.

Pharmaceutical compositions suitable for topical use on the skin arepreferably in the form of ointment, cream, lotion, paste, spray, aerosolor oil. Carriers which can be used are petrolatum, lanolin, polyethyleneglycols, alcohols and combinations of two or more of these substances.The active ingredient is generally present in a concentration of from0.1 to 15% by weight of the composition, for example from 0.5 to 2%.

Transdermal administration is also possible. Pharmaceutical compositionssuitable for transdermal uses can be in the form of single plasterswhich are suitable for long-term close contact with the patient'sepidermis. Such plasters suitably contain the active ingredient in anaqueous solution which is buffered where appropriate, dissolved and/ordispersed in an adhesive or dispersed in a polymer. A suitable activeingredient concentration is about 1% to 35%, preferably about 3% to 15%.A particular possibility is for the active ingredient to be released byelectrotransport or iontophoresis as described, for example, inPharmaceutical Research, 2(6): 318 (1986).

The compounds of the formula I are distinguished by favorable effects onmetabolic disorders. They beneficially influence lipid and sugarmetabolism, in particular they lower the triglyceride level and aresuitable for the prevention and treatment of type II diabetes andatheriosclerosis and the diverse sequalae thereof.

Pharmaceutical Combinations

The compounds of the invention can be administered alone or incombination with one or more additional active pharmaceutical compounds.In particular, the compounds of the invention can be administered incombination with active ingredients having a similar pharmacologicalaction. For example, they can be administered in combination with activeingredients which are also effective in the treatment of metabolicdisturbances or disorders frequently associated therewith. Examples ofsuch pharmaceutical actives are:

-   -   1. medicaments which lower blood glucose, i.e., anti-diabetics,    -   2. active ingredients for the treatment of dyslipidemias,    -   3. anti-atherosclerotic medicaments,    -   4. anti-obesity agents,    -   5. anti-inflammatory active ingredients    -   6. active ingredients for the treatment of malignant tumors    -   7. anti-thrombotic active ingredients    -   8. active ingredients for the treatment of high blood pressure    -   9. active ingredients for the treatment of heart failure and    -   10. active ingredients for the treatment of complications caused        by diabetes or associated with diabetes.    -   11. active ingredients for the treatment of neurodegenerative        diseases    -   12. active ingredients for the treatment of disorders of the        central nervous system    -   13. active ingredients for the treatment of drug, nicotine and        alcohol addiction    -   14. analgesics

They can be combined with the compounds of the invention of the formulaI in particular for a synergistic enhancement of activity.Administration of the active ingredient combination can take placeeither by separate administration of the active ingredients to thepatient or in the form of combination products in which a plurality ofactive ingredients are present in one pharmaceutical preparation.

Particularly suitable further active ingredients for the combinationpreparations are: All antidiabetics mentioned in the Rote Liste 2006,Chapter 12; all slimming agents/appetite suppressants mentioned in theRote Liste 2006, Chapter 1; all lipid-lowering agents mentioned in theRote Liste 2006, Chapter 58. They can be combined with the compound ofthe formula I according to the invention in particular for a synergisticenhancement of activity. The active compound combination can beadministered either by separate administration of the active compoundsto the patient or in the form of combination preparations in which aplurality of active compounds are present in a pharmaceuticalpreparation. Most of the active compounds listed below are disclosed inUSP Dictionary of USAN and International Drug Names, US Pharmacopeia,Rockville 2001.

Anti-diabetics include insulin and insulin derivatives, such as, forexample, Lantus® (see www.lantus.com) or HMR 1964 or those described inWO2005005477 (Novo Nordisk), fast-acting insulins (see U.S. Pat. No.6,221,633), inhalable insulins, such as, for example, Exubera® or oralinsulins, such as, for example, IN-105 (Nobex) or Oral-lyn™ (GenerexBiotechnology), GLP-1 derivatives, such as, for example, Exenatide,Liraglutide or those disclosed in WO 98/08871 or WO2005027978 by NovoNordisk A/S, in WO 01/04156 by Zealand or in WO 00/34331 byBeaufour-lpsen, pramlintide acetate (Symlin; Amylin Pharmaceuticals),and also orally effective hypoglycemic active ingredients.

The active compounds preferably include

sulfonylureas,

biguanidines,

meglitinides,

oxadiazolidinediones,

thiazolidinediones,

glucosidase inhibitors,

inhibitors of glycogen phosphorylase,

glucagon antagonists,

glucokinase activators,

inhibitors of fructose-1,6-bisphosphatase,

modulators of the glucose transporter 4 (GLUT4),

inhibitors of glutamine:fructose-6-phosphate amidotransferase (GFAT),

GLP-1 agonists,

potassium channel openers, such as, for example, those disclosed in WO97/26265 and WO 99/03861 by Novo Nordisk A/S,

inhibitors of dipeptidylpeptidase IV (DPP-IV),

insulin sensitizers,

inhibitors of liver enzymes involved in the stimulation ofgluconeogenesis and/or

glycogenolysis,

modulators of glucose uptake, glucose transport and glucose backresorption,

inhibitors of 11β-HSD1,

inhibitors of protein tyrosine phosphatase 1B (PTP1B),

modulators of the sodium/glucose cotransporter 1 or 2 (SGLT1, SGLT2),

compounds which alter lipid metabolism, such as antihyperlipidemicactive ingredients and antilipidemic active ingredients,

compounds which reduce food intake or food absorption,

compounds which increase thermogenesis,

PPAR and RXR modulators and

active ingredients which act on the ATP-dependent potassium channel ofthe beta cells.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a HMGCoA reductase inhibitor, such assimvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin,cerivastatin, rosuvastatin or L-659699.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a cholesterol resorption inhibitor,such as, for example, ezetimibe, tiqueside, pamaqueside, FM-VP4(sitostanol/campesterol ascorbyl phosphate; Forbes Medi-Tech,WO2005042692), MD-0727 (Microbia Inc., WO2005021497) or with compoundsas described in WO2002066464 (Kotobuki Pharmaceutical Co. Ltd.),WO2005062824 (Merck & Co.) or WO2005061451 and WO2005061452 (AstraZenecaAB).

In another embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR gamma agonist, such as, forexample, rosiglitazone, pioglitazone, JTT-501, G1262570, R-483 or CS-011(rivoglitazone).

In another embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR alpha agonist, such as, forexample, GW9578, GW-590735, K-111, LY-674, KRP-101 or DRF-10945.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a mixed PPAR alpha/gamma agonist, suchas, for example, muraglitazar, tesaglitazar, naveglitazar, LY-510929,ONO-5129, E-3030 or as described in WO00/64888, WO00/64876, WO03/020269,WO2004075891, WO2004076402, WO2004075815, WO2004076447, WO2004076428,WO2004076401, WO2004076426, WO2004076427, WO2006018118, WO2006018115,and WO2006018116 or in J. P. Berger et al., TRENDS in PharmacologicalSciences 28(5), 244-251, 2005.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR delta agonist, such as, forexample, GW-501516 or as described in WO2005097762, WO2005097786,WO2005097763, and WO2006029699.

In another embodiment of the invention, the compound of the formula I isadministered in combination with metaglidasen or with MBX-2044 or otherpartial PPAR gamma agonists/antagonists.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a fibrate, such as, for example,fenofibrate, clofibrate or bezafibrate.

In another embodiment of the invention, the compound of the formula I isadministered in combination with an MTP inhibitor, such as, for example,implitapide, BMS-201038, R-103757 or those described in WO2005085226.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a CETP inhibitor, such as, for example,torcetrapib or JTT-705.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a bile acid resorption inhibitor (see,for example, U.S. Pat. No. 6,245,744, U.S. Pat. No. 6,221,897 orWO00/61568), such as, for example, HMR 1741 or those described in DE 102005 033099.1 and DE 10 2005 033100.9.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a polymeric bile acid adsorber, suchas, for example, cholestyramine or colesevelam.

In another embodiment of the invention, the compound of the formula I isadministered in combination with an LDL receptor inducer (see U.S. Pat.No. 6,342,512), such as, for example, HMR1171, HMR1586 or thosedescribed in WO2005097738.

In another embodiment, the compound of the formula I is administered incombination with Omacor® (omega-3 fatty acids; highly concentrated ethylesters of eicosapentaenoic acid and docosahexaenoic acid).

In another embodiment of the invention, the compound of the formula I isadministered in combination with an ACAT inhibitor, such as, forexample, avasimibe.

In another embodiment of the invention, the compound of the formula I isadministered in combination with an antioxidant, such as, for example,OPC-14117, probucol, tocopherol, ascorbic acid, β-carotene or selenium.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a vitamin, such as, for example,vitamin B6 or vitamin B12.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a lipoprotein lipase modulator, suchas, for example, ibrolipim (NO-1886).

In another embodiment of the invention, the compound of the formula I isadministered in combination with an ATP-citrate lyase inhibitor, suchas, for example, SB-204990.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a squalene synthetase inhibitor, suchas, for example, BMS-188494 or as described in WO2005077907.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipoprotein(a) antagonist, such as,for example, gemcabene (CI-1027).

In another embodiment of the invention, the compound of the formula I isadministered in combination with an HM74A receptor agonists, such as,for example, nicotinic acid.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a lipase inhibitor, such as, forexample, orlistat or cetilistat (ATL-962).

In another embodiment of the invention, the compound of the formula I isadministered in combination with insulin.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a sulfonylurea, such as, for example,tolbutamide, glibenclamide, glipizide or glimepiride.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a biguanide, such as, for example,metformin.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a meglitinide, such as, for example,repaglinide or nateglinide.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a thiazolidinedione, such as, forexample, troglitazone, ciglitazone, pioglitazone, rosiglitazone or thecompounds disclosed in WO 97/41097 by Dr. Reddy's Research Foundation,in particular5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

In another embodiment of the invention, the compound of the formula I isadministered in combination with an α-glucosidase inhibitor, such as,for example, miglitol or acarbose.

In one embodiment of the invention, the compound of the formula i isadministered in combination with an active ingredient which acts on theATP-dependent potassium channel of the beta cells, such as, for example,tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.

In another embodiment of the invention, the compound of the formula I isadministered in combination with more than one of the compoundsmentioned above, for example in combination with a sulfonylurea andmetformin, a sulfonylurea and acarbose, repaglinide and metformin,insulin and a sulfonylurea, insulin and metformin, insulin andtroglitazone, insulin and lovastatin, etc.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an inhibitor of glycogen phosphorylase,such as, for example, PSN-357 or FR-258900 or those described inWO2003084922, WO2004007455, WO2005073229-31 or WO2005067932.

In another embodiment of the invention, the compound of the formula I isadministered in combination with glucagon receptor antagonists, such as,for example, A-770077, NNC-25-2504 or such as in WO2004100875 orWO2005065680.

In one embodiment of the invention, the compound of the formula I isadministered in combination with activators of glucokinase, such as, forexample, RO-4389620, LY-2121260 (WO2004063179), PSN-105, PSN-110, GKA-50or those described, for example, by Prosidion in WO2004072031,WO2004072066, WO 05103021 or WO 06016178, by Roche in WO 00058293, WO00183465, WO 00183478, WO 00185706, WO 00185707, WO 01044216, GB02385328, WO 02008209, WO 02014312, WO 0246173, WO 0248106, DE 10259786,WO 03095438, US 04067939 or WO 04052869, by Novo Nordisk in EP 1532980,WO 03055482, WO 04002481, WO 05049019, WO 05066145 or WO 05123132, byMerck/Banyu in WO 03080585, WO03097824, WO 04081001, WO 05063738 or WO05090332, by Eli Lilly in WO 04063194, or by Astra Zeneca in WO01020327, WO 03000262, WO 03000267, WO 03015774, WO 04045614, WO04046139, WO 05044801, WO 05054200, WO 05054233, WO 05056530, WO05080359, WO 05080360 or WO 05121110.

In yet another embodiment of the invention, the compound of the formulaI is administered in combination with an inhibitor of gluconeogenesis,such as, for example, FR-225654.

In one embodiment of the invention, the compound of the formula I isadministered in combination with inhibitors offructose-1,6-bisphosphatase (FBPase), such as, for example, CS-917.

In another embodiment of the invention, the compound of the formula I isadministered in combination with modulators of the glucose transporter 4(GLUT4), such as, for example, KST-48 (D.-O. Lee et al.:Arzneim.-Forsch. Drug Res. 54 (12), 835 (2004)).

In another embodiment of the invention, the compound of the formula I isadministered in combination with inhibitors ofglutamine:fructose-6-phosphate amidotransferase (GFAT), as described,for example, in WO2004101528.

In one embodiment of the invention, the compound of the formula I isadministered in combination with inhibitors of dipeptidylpeptidase IV(DPP-IV), such as, for example, vildagliptin (LAF-237), sitagliptin(MK-0431), saxagliptin ((BMS-477118), GSK-823093, PSN-9301, SYR-322,SYR-619, TA-6666, TS-021, GRC-8200, GW-825964X or as described inWO2003074500, WO2003106456, WO200450658, WO2005058901, WO2005012312,WO2005/012308, PCT/EP2005/007821, PCT/EP2005/008005, PCT/EP2005/008002,PCT/EP2005/008004, PCT/EP2005/008283, DE 10 2005 012874.2 or DE 10 2005012873.4.

In another embodiment of the invention, the compound of the formula I isadministered in combination with inhibitors of 11-beta-hydroxysteroiddehydrogenase-1 (11β-HSD1), such as, for example, BVT-2733 or thosedescribed, for example, in WO200190090-94, WO200343999, WO2004112782,WO200344000, WO200344009, WO2004112779, WO2004113310, WO2004103980,WO2004112784, WO2003065983, WO2003104207, WO2003104208, WO2004106294,WO2004011410, WO2004033427, WO2004041264, WO2004037251, WO2004056744,WO2004065351, WO2004089367, WO2004089380, WO2004089470-71, WO2004089896,WO2005016877 or WO2005097759.

In one embodiment of the invention, the compound of the formula I isadministered in combination with inhibitors of protein tyrosinephosphatase 1B (PTP1B), as described, for example, in WO200119830-31,WO200117516, WO2004506446, WO2005012295, PCT/EP2005/005311,PCT/EP2005/005321, PCT/EP2005/007151, PCT/EP200/5 or DE 10 2004060542.4.

In another embodiment of the invention, the compound of the formula I isadministered in combination with modulators of the sodium/glucosecotransporter 1 or 2 (SGLT1, SGLT2), such as, for example, KGA-2727,T-1095 and SGL-0010 or as described, for example, in WO2004007517,WO200452903, WO200452902, WO2005121161, WO2005085237, JP2004359630 or byA. L. Handlon in Expert Opin. Ther. Patents (2005) 15(11), 1531-1540.

In one embodiment of the invention, the compound of the formula I isadministered in combination with inhibitors of hormone-sensitive lipase(HSL), such as those described, for example, in WO01/17981, WO01/66531,WO2004035550, WO2005073199 or WO03/051842.

In another embodiment of the invention, the compound of the formula I isadministered in combination with inhibitors of acetyl-CoA carboxylase(ACC) such as those described, for example, in WO199946262, WO200372197,WO2003072197 or WO2005044814.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an inhibitor of phosphoenolpyruvatecarboxykinase (PEPCK), such as those described, for example, inWO2004074288.

In another embodiment of the invention, the compound of the formula I isadministered in combination with an inhibitor of glycogen synthasekinase-3 beta (GSK-3 beta), such as those described, for example, inUS2005222220, WO2004046117, WO2005085230, WO2005111018, WO2003078403,WO2004022544, WO2003106410, WO2005058908, US2005038023, WO2005009997,US2005026984, WO2005000836, WO2004106343, EP 1460075, WO2004014910,WO2003076442, WO2005087727 or WO2004046117.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an inhibitor of protein kinase C beta(PKC beta), such as, for example, ruboxistaurin.

In another embodiment of the invention, the compound of the formula I isadministered in combination with an endothelin-A receptor antagonist,such as, for example, avosentan (SPP-301).

In one embodiment of the invention, the compound of the formula I isadministered in combination with inhibitors of “1-kappaB kinase” (IKKinhibitors), such as those described, for example, in WO2001000610,WO2001030774, WO2004022553 or WO2005097129.

In one embodiment of the invention, the compound of the formula I isadministered in combination with modulators of the glucocorticoidreceptor as described, for example, in WO2005090336.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with CART modulators (see“Cocaine-amphetamine-regulated transcript influences energy metabolism,anxiety and gastric emptying in mice” Asakawa, A. et al.: Hormone andMetabolic Research (2001), 33(9), 554-558); NPY antagonists such as, forexample,{4-[(4-aminoquinazolin-2-ylamino)methyl]-cyclohexylmethyl}naphthalene-1-sulfonamidehydrochloride (CGP 71683A); peptide YY 3-36 (PYY3-36) or analogouscompounds, such as, for example, CJC-1682 (PYY3-36 conjugated with humanserum albumin via Cys34), CJC-1643 (derivative of PYY3-36 whichconjugates in vivo to serum albumin) or those described in WO2005080424;cannabinoid receptor 1 antagonists, such as, for example, rimonabant,SR147778 or those described, for example, in EP 0656354, WO 00/15609, WO02/076949, WO2005080345, WO2005080328, WO2005080343, WO2005075450,WO2005080357, WO200170700, WO2003026647-48, WO200302776, WO2003040107,WO2003007887, WO2003027069, U.S. Pat. No. 6,509,367, WO200132663,WO2003086288, WO2003087037, WO2004048317, WO2004058145, WO2003084930,WO2003084943, WO2004058744, WO2004013120, WO2004029204, WO2004035566,WO2004058249, WO2004058255, WO2004058727, WO2004069838, US20040214837,US20040214855, US20040214856, WO2004096209, WO2004096763, WO2004096794,WO2005000809, WO2004099157, US20040266845, WO2004110453, WO2004108728,WO2004000817, WO2005000820, US20050009870, WO200500974, WO2004111033-34,WO200411038-39, WO2005016286, WO2005007111, WO2005007628, US20050054679,WO2005027837, WO2005028456, WO2005063761-62, WO2005061509 orWO2005077897; MC4 agonists (for example[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]-1-amino-1,2,3,4-tetrahydro-naphthalene-2-carboxamide;(WO 01/91752)) or LB53280, LB53279, LB53278 or THIQ, MB243, RY764,CHIR-785, PT-141 or those described in WO2005060985, WO2005009950,WO2004087159, WO2004078717, WO2004078716, WO2004024720, US20050124652,WO2005051391, WO2004112793, WOUS20050222014, US20050176728,US20050164914, US20050124636, US20050130988, US20040167201,WO2004005324, WO2004037797, WO2005042516, WO2005040109, WO2005030797,US20040224901, WO200501921, WO200509184, WO2005000339, EP1460069,WO2005047253, WO2005047251, EPI 538159, WO2004072076, WO2004072077 orWO2006024390; orexin receptor antagonists (for example1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea hydrochloride(SB-334867-A) or those described, for example, in WO200196302,WO200185693, WO2004085403 or WO2005075458); histamine H3 receptoragonists (for example3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)-propan-1-oneoxalic acid salt (WO 00/63208) or those described in WO200064884,WO2005082893);

CRF antagonists (for example[2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine(WO 00/66585));

CRF BP antagonists (for example urocortin);

urocortin agonists; β3 agonists (such as, for example,1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]ethanolhydrochloride (WO 01/83451)); MSH (melanocyte-stimulating hormone)agonists; MCH (melanin-concentrating hormone) receptor antagonists (suchas, for example, NBI-845, A-761, A-665798, A-798, ATC-0175, T-226296,T-71, GW-803430 or those compounds described in WO2003/15769,WO2005085200, WO2005019240, WO2004011438, WO2004012648, WO2003015769,WO2004072025, WO2005070898, WO2005070925, WO2006018280, WO2006018279,WO2004039780, WO2003033476, WO2002006245, WO2002002744, WO2003004027 orFR2868780);CCK-A agonists (such as, for example,{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}aceticacid trifluoroacetic acid salt (WO 99/15525), SR-146131 (WO 0244150) orSSR-125180);serotonin reuptake inhibitors (for example dexfenfluramine);mixed serotonin- and noradrenergic compounds (for example WO 00/71549);5-HT receptor agonists, for example 1-(3-ethylbenzofuran-7-yl)piperazineoxalic acid salt (WO 01/09111);5-HT2C receptor agonists (such as, for example, APD-356, BVT-933 orthose described in WO200077010, WO20077001-02, WO2005019180,WO2003064423, WO200242304 or WO2005082859);5-HT6 receptor antagonists, such as described, for example, inWO2005058858; bombesin receptor agonists (BRS-3 agonists); galaninreceptor antagonists;growth hormone (for example human growth hormone or AOD-9604);growth hormone releasing compounds (tert-butyl6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate(WO 01/85695));growth hormone secretagog receptor antagonists (ghrelin antagonists)such as, for example, A-778193 or those described in WO2005030734;TRH agonists (see, for example, EP 0 462 884);uncoupling protein 2 or 3 modulators; leptin agonists (see for exampleLee, Daniel W.;Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptinagonists as a potential approach to the treatment of obesity. Drugs ofthe Future (2001), 26(9), 873-881);DA agonists (bromocriptine or Doprexin);lipase/amylase inhibitors (as described, for example, in WO 00/40569);inhibitors of diacylglycerol O-acyltransferases (DGATs) such asdescribed, for example, in US2004/0224997, WO2004094618, WO200058491,WO2005044250, WO2005072740, JP2005206492 or WO2005013907;inhibitors of fatty acid synthase (FAS) such as, for example, C75 orthose described in WO2004005277;oxyntomodulin;oleoyl-estroneor thyroid hormone receptor agonists, such as, for example, KB-2115 orthose described in WO20058279, WO200172692, WO200194293, WO2003084915,WO2004018421 or WO2005092316.

In yet another embodiment of the invention, the additionalpharmaceutical active is leptin;

see for example “Perspectives in the therapeutic use of leptin”,Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinionon Pharmacotherapy (2001), 2(10), 1615-1622.

In one embodiment of the invention, the further active ingredient isdexamphetamine or amphetamine.

In one embodiment of the invention, the further active ingredient isfenfluramine or dexfenfluramine.

In another embodiment of the invention, the further active ingredient issibutramine.

In one embodiment of the invention, the further active ingredient ismazindol or phentermine.

In another embodiment, the compounds of the formula I are administeredin combination with bulking agents, preferably insoluble bulking agents(see, for example, carob/Caromaxe (Zunft H J; et al., Carob pulppreparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY(2001 September-October), 18(5), 230-6). Caromax is a carob-containingproduct from Nutrinova, Nutrition Specialties & Food Ingredients GmbH,Industriepark Höchst, 65926 Frankfurt/Main). Combination with Caromax®is possible in one preparation or by separate administration ofcompounds of the formula I and Caromax®. Caromax® can in this connectionalso be administered in the form of food products such as, for example,in bakery products or muesli bars.

In one embodiment of the invention, the compound of the formula I isadministered in combination with PDE (phosphodiesterase) inhibitors, asdescribed, for example, in WO2003/077949 or WO2005012485.

The additional pharmaceutical active in another embodiment of theinvention, the compound of the formula I is administered in combinationwith NAR-1 (nicotinic acid receptor) agonists as described, for example,in WO2004094429.

In one embodiment of the invention, the compound of the formula I isadministered in combination with CB2 (cannabinoid receptor) agonists asdescribed, for example, in US2005/143448.

In one embodiment of the invention, the compound of the formula I isadministered in combination with histamine 1 agonists as described, forexample, in WO2005101979.

In one embodiment of the invention, the compound of the formula I isadministered in combination with bupropion, as described inWO2006017504.

In another embodiment of the invention, the compound of the formula I isadministered in combination with opioid antagonists as described, forexample, in WO2005107806 or WO2004094429.

In one embodiment of the invention, the compound of the formula I isadministered in combination with neutral endopeptidase inhibitors asdescribed, for example, in WO200202513, WO2002/06492, WO 2002040008,WO2002040022 or WO2002047670.

In one embodiment of the invention, the compound of the formula I isadministered in combination with NPY inhibitors (neuropeptide Y) asdescribed, for example, in WO2002047670.

In one embodiment of the invention, the compound of the formula I isadministered in combination with sodium/hydrogen exchange inhibitors asdescribed, for example, in WO2003092694.

In one embodiment of the invention, the compound of the formula I isadministered in combination with modulators of the glucocorticoidreceptor as described, for example, in WO2005090336.

In one embodiment of the invention, the compound of the formula I isadministered in combination with nicotine receptor agonists asdescribed, for example, in WO2004094429.

In one embodiment of the invention, the compound of the formula I isadministered in combination with NRIs (norepinephrine reuptakeinhibitors) as described, for example, in WO2002053140.

In one embodiment of the invention, the compound of the formula I isadministered in combination with MOA (E-beta-methoxyacrylate), such as,for example, segeline, or as described, for example, in WO2002053140.

In one embodiment of the invention, the compound of the formula I isadministered in combination with antithrombotic active ingredients, suchas, for example, clopidogrel.

It is to be understood that each suitable combination of the compoundsaccording to the invention with one or more of the compounds mentionedabove and optionally one or more further pharmacologically activesubstances is meant to be included in the scope of the presentinvention.

The formulae for some of the development codes mentioned above are givenbelow.

The activity of the compounds was tested by a determination of EC50values of PPAR agonists in the cellular PPARalpha assay. The potency ofsubstances which bind to human PPARalpha and activate it in an agonisticmanner is analyzed using a stably transfected HEK cell line (HEK=humanembryo kidney) which is referred to here as PPARalpha reporter cellline. It contains two genetic elements, a luciferase reporter element(pdeltaM-GAL4-Luc-Zeo) and a PPARalpha fusion protein(GR-GAL4-humanPPARalpha-LBD) which mediates expression of the luciferasereporter element depending on a PPARalpha ligand. The stably andconstitutively expressed fusion protein GR-GAL4-humanPPARalpha-LBD bindsin the cell nucleus of the PPARalpha reporter cell line via the GAL4protein portion to the GAL4 DNA binding motifs 5′-upstream of theluciferase reporter element which is stably integrated in the genome ofthe cell line. There is only weak expression of the luciferase reportergene in the absence of a PPARalpha ligand if fatty acid-depleted fetalcalf serum (cs-FCS) is used in the assay. PPARalpha ligands bind andactivate the PPARalpha fusion protein and thereby stimulate theexpression of the luciferase reporter gene. The luciferase which isformed can be detected by means of chemiluminescence via an appropriatesubstrate.

Construction of the PPARalpha Reporter Cell Line

The PPARalpha reporter cell line was prepared in two stages. Firstly,the luciferase reporter element was constructed and stably transfectedinto HEK cells. For this purpose, five binding sites of the yeasttranscription factor GAL4 (Accession # AF264724) were cloned in5′-upstream of a 68 bp-long minimal MMTV promoter (Accession #V01175).The minimal MMTV promoter section contains a CCMT box and a TATA elementin order to enable efficient transcription by RNA polymerase II. Thecloning and sequencing of the GAL4-MMTV construct took place in analogyto the description of Sambrook J. et. al. (Molecular cloning, ColdSpring Harbor Laboratory Press, 1989). Then the complete Photinuspyralis gene (Accession #M15077) was cloned in 3′-downstream of theGAL4-MMTV element. After sequencing, the luciferase reporter elementconsisting of five GAL4 binding sites, MMTV promoter and luciferase genewas recloned into a plasmid which confers zeocin resistance in order toobtain the plasmid pdeltaM-GAL4-Luc-Zeo. This vector was transfectedinto HEK cells in accordance with the statements in Ausubel, F. M. etal. (Current protocols in molecular biology, Vol. 1-3, John Wiley &Sons, Inc., 1995). Then zeocin-containing medium (0.5 mg/ml) was used toselect a suitable stable cell clone which showed very low basalexpression of the luciferase gene.

In a second step, the PPARalpha fusion protein(GR-GAL4-humanPPARalpha-LBD was introduced into the stable cell clonedescribed. For this purpose, initially the cDNA coding for theN-terminal 76 amino acids of the glucocorticoid receptor (Accession#P04150) was linked to the cDNA section coding for amino acids 1-147 ofthe yeast transcription factor GAL4 (Accession #P04386). The cDNA of theligand-binding domain of the human PPARalpha receptor (amino acidsS167-Y468; Accession #S74349) was cloned in at the 3′-end of thisGR-GAL4 construct. The fusion construct prepared in this way(GR-GAL4-humanPPARalpha-LBD) was recloned into the plasmid pcDNA3(Invitrogen) in order to enable constitutive expression therein by thecytomegalovirus promoter. This plasmid was linearized with a restrictionendonuclease and stably transfected into the previously described cellclone containing the luciferase reporter element. The finished PPARalphareporter cell line which contains a luciferase reporter element andconstitutively expresses the PPARalpha fusion protein (GR-GAL4-humanPPARalpha-LBD) was isolated by selection with zeocin (0.5 mg/ml) andG418 (0.5 mg/ml).

Assay procedure.—The activity of PPARalpha agonists is determined in a3-day assay which is described below:

Day 1

The PPARalpha reporter cell line is cultivated to 80% confluence in DMEM(#41965-039, Invitrogen) which is mixed with the following additions:10% cs-FCS (fetal calf serum; #SH-30068.03, Hyclone), 0.5 mg/ml zeocin(#R250-01, Invitrogen), 0.5 mg/ml G418 (#10131-027, Invitrogen), 1%penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mML-glutamine (#25030-024, Invitrogen). The cultivation takes place instandard cell culture bottles (#353112, Becton Dickinson) in a cellculture incubator at 37° C. in the presence of 5% CO2. The 80%-confluentcells are washed once with 15 ml of PBS (#14190-094, Invitrogen),treated with 3 ml of trypsin solution (#25300-054, Invitrogen) at 37° C.for 2 min, taken up in 5 ml of the DMEM described and counted in a cellcounter. After dilution to 500.000 cells/ml, 35,000 cells are seeded ineach well of a 96 well microtiter plate with a clear plastic base(#3610, Corning Costar). The plates are incubated in the cell cultureincubator at 37° C. and 5% CO2 for 24 h.

Day 2

PPARalpha agonists to be tested are dissolved in DMSO in a concentrationof 10 mM. This stock solution is diluted in DMEM (#41965-039,Invitrogen) which is mixed with 5% cs-FCS (#SH-30068.03, Hyclone), 2 mML-glutamine (#25030-024, Invitrogen) and the previously describedantibiotics (zeocin, G418, penicillin and streptomycin). Test substancesare tested in 11 different concentrations in the range from 10 μM to 100μM. More potent compounds are tested in concentration ranges from 1 μMto 10 μM or between 100 nM and 1 μM.

The medium of the PPARalpha reporter cell line seeded on day 1 iscompletely removed by aspiration, and the test substances diluted inmedium are immediately added to the cells. The dilution and addition ofthe substances is carried out by a robot (Beckman FX). The final volumeof the test substances diluted in medium is 100 μl per well of a 96 wellmicrotiter plate. The DMSO concentration in the assay is less than 0.1%v/v in order to avoid cytotoxic effects of the solvent.

Each plate was charged with a standard PPARalpha agonist, which waslikewise diluted in 11 different concentrations, in order to demonstratethe functioning of the assay in each individual plate. The assay platesare incubated in an incubator at 37° C. and 5% CO2 for 24 h.

Day 3

The PPARalpha reporter cells treated with the test substances areremoved from the incubator, and the medium is aspirated off. The cellsare lyzed by pipetting 50 μl of Bright Glo reagent (from Promega) intoeach well of a 96 well microtiter plate. After incubation at roomtemperature in the dark for 10 minutes, the microtiter plates aremeasured in the luminometer (Trilux from Wallac). The measuring time foreach well of a microtiter plate is 1 sec.

Evaluation

The raw data from the luminometer are transferred into a Microsoft Excelfile. Dose-effect plots and EC50 values of PPAR agonists are calculatedusing the XL.Fit program as specified by the manufacturer (IDBS).

PPARalpha EC50 values in the range from 100 nM to >10 μM were measuredfor the PPAR agonists of Examples 1 to 19 described in this application.Compounds of the invention of the formula I activate the PPARalphareceptor.

Determination of EC50 values of PPAR agonists in the cellular PPARdeltaassay

Principle

The potency of substances which bind to human PPARdelta and activate itin an agonistic manner is analyzed using a stably transfected HEK cellline (HEK=human embryo kidney) which is referred to here as PPARdeltareporter cell line. In analogy to the assay described for PPARalpha, thePPARdelta reporter cell line also contains two genetic elements, aluciferase reporter element (pdeltaM-GAL4-Luc-Zeo) and a PPARdeltafusion protein (GR-GAL4-humanPPARdelta-LBD) which mediates expression ofthe luciferase reporter element depending on a PPARdelta ligand. Thestably and constitutively expressed fusion proteinGR-GAL4-humanPPARdelta-LBD binds in the cell nucleus of the PPARdeltareporter cell line via the GAL4 protein portion to the GAL4 DNA bindingmotifs 5′-upstream of the luciferase reporter element which is stablyintegrated in the genome of the cell line. There is only littleexpression of the luciferase reporter gene in the absence of a PPARdeltaligand if fatty acid-depleted fetal calf serum (cs-FCS) is used in theassay. PPARdelta ligands bind and activate the PPARdelta fusion proteinand thereby stimulate expression of the luciferase reporter gene. Theluciferase which is formed can be detected by means of chemiluminescencevia an appropriate substrate.

Construction of the PPARdelta Reporter Cell Line

The production of the stable PPARdelta reporter cell line is based on astable HEK-cell clone which was stably transfected with a luciferasereporter element. This step was already described above in the section“construction of the PPARalpha reporter cell line”. In a second step,the PPARdelta fusion protein (GR-GAL4-humanPPARdelta-LBD was stablyintroduced into this cell clone. For this purpose, the cDNA coding forthe N-terminal 76 amino acids of the glucocorticoid receptor (Accession#P04150) was linked to the cDNA section coding for amino acids 1-147 ofthe yeast transcription factor GAL4 (Accession #P04386). The cDNA of theligand-binding domain of the human PPARdelta receptor (amino acidsS139-Y441; Accession #L07592) was cloned in at the 3′-end of thisGR-GAL4 construct. The fusion construct prepared in this way(GR-GAL4-humanPPARdelta-LBD) was recloned into the plasmid pcDNA3(Invitrogen) in order to enable constitutive expression by thecytomegalovirus promoter. This plasmid was linearized with a restrictionendonuclease and stably transfected into the previously described cellclone containing the luciferase reporter element. The resultingPPARdelta reporter cell line which contains a luciferase reporterelement and constitutively expresses the PPARdelta fusion protein(GR-GAL4-human PPARdelta-LBD) was isolated by selection with zeocin (0.5mg/ml) and G418 (0.5 mg/ml).

Assay Procedure and Evaluation

The activity of PPARdelta agonists is determined in a 3-day assay inexact analogy to the procedure already described for the PPARalphareporter cell line except that the PPARdelta reporter cell line and aspecific PPARdelta agonist was used as a standard to control testefficacy. PPARdelta EC50 values in the range from 200 nM to >10 μM weremeasured for the PPAR agonists of Examples 1 to 19 described in thisapplication. Compounds of the invention of the formula I activate thePPARdelta receptor.

Determination of EC50 Values of PPAR Agonists in the Cellular PPARgammaAssay

A transient transfection system is employed to determine the cellularPPARgamma activity of PPAR agonists. It is based on the use of aluciferase reporter plasmid (pGL3basic-5xGAL4-TK) and of a PPARgammaexpression plasmid (pcDNA3-GAL4-humanPPARgammaLBD). Both plasmids aretransiently transfected into human embryonic kidney cells (HEK cells).There is then expression in these cells of the fusion proteinGAL4-humanPPARgammaLBD which binds to the GAL4 binding sites of thereporter plasmid. In the presence of a PPARgamma-active ligand, theactivated fusion protein GAL4-humanPPARgammaLBD induces expression ofthe luciferase reporter gene, which can be detected in the form of achemiluminescence signal after addition of a luciferase substrate. As adifference from the stably transfected PPARalpha reporter cell line, inthe cellular PPARgamma assay the two components (luciferase reporterplasmid and PPARgamma expression plasmid) are transiently transfectedinto HEK cells because stable and permanent expression of the PPARgammafusion protein is cytotoxic.

Construction of the Plasmids

The luciferase reporter plasmid pGL3basic-5xGAL4-TK is based on thevector pGL3basic from Promega. The reporter plasmid is prepared bycloning five binding sites of the yeast transcription factor GAL4 (eachbinding site with the sequence 5′-CTCGGAGGACAGTACTCCG-3′), together witha 160 bp-long thymidine kinase promoter section (Genbank Accession#AF027128) 5′-upstream into pGL3basic. 3′-downstream of the thymidinekinase promoter is the complete luciferase gene from Photinus pyralis(Genbank Accession #M15077) which is already a constituent of theplasmid pGL3basic used. The cloning and sequencing of the reporterplasmid pGL3basic-5xGAL4-TK took place in analogy to the description inSambrook J. et. al. (Molecular cloning, Cold Spring Harbor LaboratoryPress, 1989).

The PPARgamma expression plasmid pcDNA3-GAL4-humanPPARgammaLBD wasprepared by first cloning the cDNA coding for amino acids 1-147 of theyeast transcription factor GAL4 (Genbank Accession #P04386) into theplasmid pcDNA3 (from Invitrogen) 3′-downstream of the cytomegaloviruspromoter. Subsequently, the cDNA of the ligand-binding domain (LBD) ofthe human PPARgamma receptor (amino acids 1152-Y475; Accession#g1480099) 3′-downstream of the GAL4 DNA binding domain. Cloning andsequencing of the PPARgamma expression plasmidpcDNA3-GAL4-humanPPARgammaLBD again took place in analogy to thedescription in Sambrook J. et. al. (Molecular cloning, Cold SpringHarbor Laboratory Press, 1989). Besides the luciferase reporter plasmidpGL3basic-5xGAL4-TK and the PPARgamma expression plasmidpcDNA3-GAL4-humanPPARgammaLBD, also used for the cellular PPARgammaassay are the reference plasmid pRL-CMV (from Promega) and the plasmidpBluescript SK(+) from Stratagene. All four plasmids were prepared usinga plasmid preparation kit from Qiagen, which ensured a plasmid qualitywith a minimal endotoxin content, before transfection into HEK cells.

The activity of PPARgamma agonists was then determined in a 4-day assaywhich is described below. Before the transfection, HEK cells arecultivated in DMEM (#41965-039, Invitrogen) which is mixed with thefollowing additions: 10% FCS (#16000-044, Invitrogen), 1%penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mML-glutamine (#25030-024, Invitrogen).

Day 1

Firstly, solution A, a transfection mixture which contains all fourplasmids previously described in addition to DMEM, is prepared. Thefollowing amounts are used to make up 3 ml of solution A for each 96well microtiter plate for an assay: 2622 μl of antibiotic- andserum-free DMEM (#41965-039, Invitrogen), 100 μl of reference plasmidpRL-CMV (1 ng/μl), 100 μl of luciferase reporter plasmidpGL3basic-5xGAL4-TK (10 ng/μl), 100 μl of PPARgamma expression plasmidpcDNA3-GAL4-humanPPARgammaLBD (100 ng/μl) and 78 μl of plasmidpBluescript SK(+) (500 ng/μl). Then 2 ml of solution B are prepared bymixing 1.9 ml of DMEM (#41965-039, Invitrogen) with 100 μl of PolyFecttransfection reagent (from Qiagen) for each 96 well microtiter plate.Subsequently, 3 ml of solution A are mixed with 2 ml of solution B togive 5 ml of solution C, which is thoroughly mixed by multiple pipettingand incubated at room temperature for 10 min.

80%-confluent HEK cells from a cell culture bottle with a capacity of175 cm2 are washed once with 15 ml of PBS (#14190-094, Invitrogen) andtreated with 3 ml of trypsin solution (#25300-054, Invitrogen) at 37° C.for 2 min. The cells are then taken up in 15 ml of DMEM (#41965-039,Invitrogen) which is mixed with 10% FCS (#16000-044, Invitrogen), 1%penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mML-glutamine (#25030-024, Invitrogen). After the cell suspension has beencounted in a cell counter, the suspension is diluted to 250,000cells/ml. 15 ml of this cell suspension are mixed with 5 ml of solutionC for one microtiter plate. 200 μl of the suspension are seeded in eachwell of a 96 well microtiter plate with a clear plastic base (#3610,Corning Costar). The plates are incubated in a cell culture incubator at37° C. and 5% CO2 for 24 h.

Day 2

PPAR agonists to be tested are dissolved in DMSO in a concentration of10 mM. This stock solution is diluted in DMEM (#41965-039, Invitrogen)which is mixed with 2% Ultroser (#12039-012, Biosepra), 1%penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mML-glutamine (#25030-024, Invitrogen). Test substances are tested in atotal of 11 different concentrations in the range from 10 μM to 100 μM.More potent compounds are tested in concentration ranges from 1 μM to 10μM.

The medium of the HEK cells transfected and seeded on day 1 iscompletely removed by aspiration, and the test substances diluted inmedium are immediately added to the cells. The dilution and addition ofthe substances is carried out by a robot (Beckman FX). The final volumeof the test substances diluted in medium is 100 μl per well of a 96 wellmicrotiter plate. Each plate is charged with a standard PPARgammaagonist, which is likewise diluted in 11 different concentrations, inorder to demonstrate the functioning of the assay in each individualplate. The assay plates are incubated in an incubator at 37° C. and 5%CO2.

Day 4

After removal of the medium by aspiration, 50 μl of Dual-Glo™ reagent(Dual-Glo™ Luciferase Assay System; Promega) are added to each well inaccordance with the manufacturer's instructions in order to lyze thecells and provide the substrate for the firefly luciferase (Photinuspyralis) formed in the cells. After incubation at room temperature inthe dark for 10 minutes, the firefly luciferase-mediatedchemiluminescence is measured in a measuring instrument (measuringtime/well 1 sec; Trilux from Wallac). Then 50 μl of the Dual-Glo™ Stop &Glo reagent (Dual-Glo™ Luciferase Assay System; Promega) is added toeach well in order to stop the activity of the firefly luciferase andprovide the substrate for the Renilla luciferase expressed by thereference plasmid pRL-CMV. After incubation at room temperature in thedark for a further 10 minutes, a chemiluminescence mediated by theRenilla luciferase is again measured for 1 sec/well in the measuringinstrument.

Evaluation

The crude data from the luminometer are transferred into a MicrosoftExcel file. The firefly/Renilla luciferase activity ratio is determinedfor each measurement derived from one well of the microtiter plate. Thedose-effect plots and EC50 values of PPAR agonists are calculated fromthe ratios by the XL.Fit program as specified by the manufacturer(IDBS).

PPARgamma EC50 values in the range from 1 nM to >10 μM were measured forthe PPAR agonists of Examples 1 to 19 described in this application.Compounds of the invention of the formula I activate the PPARgammareceptor.

It is to be understood that each suitable combination of the compoundsaccording to formula I of the present invention with one or more of theadditional active pharmaceutical compounds mentioned above andnon-active ingredients is deemed as falling within the scope of thepresent invention. The following examples are hereby presented in orderto more fully describe and explicitly detail the manner in which oneskilled in the art might better practice and prepare the compounds andfollow the practices of the present invention. It is to be understoodhowever, that they are for illustrative purposes only and should not beconsidered as limiting the spirit and scope of the invention as setforth and recited in the claims that follow.

where R2, R3, R4, R5, R6, R7=H and p=1,and a dotted line means the point of attachment.

On ring B the dotted line means the point of attachment via z to ring A.

On ring A the left dotted line means the point of attachment via z toring B and the right dotted line means the point of attachment to—[C(R6R7)]m-.

TABLE I Example R1 q m B A Z R8 R9 1 —CH(CH3)2 1 0

bond 4-CH3 4-CF3 2 —CH(CH3)2 1 0

bond 4-CH3 3-CF3 3 —CH(CH3)2 1 0

absent H 6-OCH3 4 —CH(CH3)2 1 0

O H 4-CF3 5 —CH(CH3)2 1 0

O H 2-OCH3 6 —CH(CH3)2 1 0

bond 4-(CH2)3CH3 4-CF3 7 —CH(CH3)2 1 0

O 5-CH3 4-OPh 8 —CH(CH3)2 1 0

bond H H 9 —CH(CH3)2 0 0

bond — 4-OCH3 10 —CH(CH3)2 1 0

O 5-CH3 4-OCH3 11 —CH(CH3)2 1 0

O 5-CH3 4-Ph 12 —CH(CH3)2 1 0

absent H 5-OCH3 13 —CH(CH3)2 1 0

bond 5-H 4-OCH3 14 —CH(CH3)2 1 0

bond 5-CH2CH3 3-CF3 15 —CH(CH3)2 1 0

bond 5-CH3 4-OCF3 16 —CH(CH3)2 1 0

bond 5-CH(CH3)2 4-CF3 17 —CH(CH3)2 1 0

bond 5-CH2CH3 2-CF3 18 —CF3 1 1

bond 5-CH3 4-CF3 19 —CH(CH3)2 1 1

bond 5-CH3 4-CF3

The potency of some of the described examples are indicated in thefollowing table:

PPARdelta PPARgamma PPARalpha Example EC50 (μM) EC50 (μM) EC50 (μM] 10.37 0.05 2.90 3 0.48 0.46 4.57 4 1.13 0.46 0.54 9 0.26 0.05 1.42 120.48 n.d. n.d. 13 0.65 1.97 1.20 14 0.67 0.001 0.19Processes

The compounds of the general formula I according to the invention can beobtained as outlined to the reaction schemes below:

Process A

This process is used for synthesizing compounds of general formula A-8,where A, B, m, p, q, R1, R3, R4, R5, R6, R7, R8 and R9 are as defined.

A sodium salt of a sulfonic acid of general formula A-1 where R2 and R3are as defined is treated with thionyl chloride in a polar aproticsolvent dimethylformamide under reflux to obtain a benzenesulfonylchloride of general formula A-3. Alternatively an acetic acid phenylester of general formula A-2, where R2 and R3 are as defined is treatedwith chlorosulfonic acid to obtain the benzenesulfonyl chloride ofgeneral formula A-3. The benzenesulfonyl chloride of general formula A-3is coupled with the [1,3,4]thiadiazol-2-ylamine of general formula A-4,where R1 is as defined in pyridine with a catalytic amount ofN,N-dimethylaminopyridine to obtain the benzenesulfonyl amide of generalformula A-5. The hydrogen atom of the sulfonamide moiety of the compoundof general formula A-5 is protected, e.g. by a2-(trimethylsilyl)ethoxy-methyl protecting group (SEM), by treatmentwith 2-(trimethylsilyl)ethoxy-methyl chloride in the presence of a baseas N,N-diisopropylethylamine and catalytic amount of4-dimethylaminopyridine in a nonpolar solvent, such as dichloromethaneto obtain a compound of general formula A-5. Upon treatment with sodiumcarbonate in a polar solvent as methanol the O-acetyl group is removedto obtain the phenol of general formula A-6.

The phenol of general formula A-6 is either coupled with a halide ormesylate or tosylate of general formula BB, where FG=OMs, OTs or halideand A, B, Z, m, p, q, R4, R5, R6, R7, R8 and R9 are as defined in thepresence of a base as cesium carbonate in a solvent as dimethylformamideor with an alcohol of general formula ABB where FG=OH and A, B, Z, m, p,q, R4, R5, R6, R7, R8 and R9 are as defined under Mitsunobu reactionconditions (triphenylphosphine, diethylazodicarboxylate for instance) ina solvent as dichloromethane or tetrahydrofuran to obtain a compound ofgeneral formula A-7. The protecting group of the compound of generalformula A-7 is the removed upon treatment withtetra-N-butylammoniumfluoride in a polar solvent as tetrahydrofuran toobtain a compound of general formula A-8.

Examples 1-12 were obtained according to process A.

Other compounds can be obtained accordingly.

Process B:

This process is used for synthesizing compounds of general formula B-5,where A, B, m, p, q, R1, R3, R4, R5, R6, R7, R8 and R9 are as defined.

A phenol of general formula B-1 where R2 and R3 are as defined is eithercoupled with a halide or mesylate or tosylate of general formula BB,where FG is a halide, mesylate or tosylate and A, B, Z, m, p, q, R4, R5,R6, R7, R8 and R9 are as defined in the presence of a base as cesiumcarbonate or sodium hydride in a polar aprotic solvent asdimethylformamide or with an alcohol of general formula BB where FG=OHand A, B, Z, m, p, q, R4, R5, R6, R7, R8 and R9 are as defined underMitsunobu reaction conditions (triphenylphosphine,diethylazodicarboxylate for instance) in a solvent as dichloromethane ortetrahydrofuran to obtain a compound of general formula B-2. Thecompound of general formula B-2 is treated with chlorosulfonic acid inan apolar solvent as dichloromethane to obtain the benzenesulfonylchloride of general formula B-3. The benzenesulfonyl chloride of generalformula B-3 is coupled with the [1,3,4]thiadiazol-2-ylamine of generalformula B-4, where R1 is as defined, in pyridine with a catalytic amountof N,N-dimethylaminopyridine to obtain the sulfonyl amide of generalformula B-5.

Examples 13-19 were obtained according to process B.

Other compounds can be obtained accordingly.

Process BB:

This process is used for synthesizing building blocks of general formulaBB-2, where R4 and R5 are H and R6, R7, A, B, m, p, q, Z, R8 and R9 areas defined and BB-3 where R4 and R5 are H, FG is a halide, mesylate ortosylate and R6, R7, A, B, m, p, q, Z, R8 and R9 are as defined.

A carboxylic ester or acid of general formula BB-1 where R6, R7, R8, R9,A, Z, m, p, q, and B are as defined is reduced with a reducing agent aslithium aluminum hydride in a polar solvent as tetrahydrofuran to obtainan alcohol of general formula BB-2. The hydroxyl group of the compoundof general formula BB-2 is transformed to a leaving group (LG) as forexample a chloride, tosylate or mesylate, by methods known in the stateof the art. Other compounds can be obtained accordingly.

LIST OF ABBREVIATION

Ac acetyl AIBN 2,2′-azobis(2-methylpropionitrile) Bn benzyl BOCtert-butyl-oxy-carbonyl iBu isobutyl tBu tert-Butyl BuLi n-butyllithiumBz benzoyl Cy cyclohexyl DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCIdirect chemical ionization (MS) DCM dichloromethane DEADdiethyidiazodicarboxylate DMAP N,N-dimethylaminopyridine DMFN,N-dimethylformamide DMSO dimethylsulfoxide EE ethyl acetate eqequivalents ESI electronspray-Ionisation (MS) FG leaving group GC gaschromatography Hal halogen HPLC high performance liquid chromatographyLC-MS liquid chromatography coupled with mass-spectroscopy LG Leavinggroup Me methyl MeCN acetonitrile MS mass-spectroscopy MS 4A molecularsieves four angström MsCl methanesulfonylchloride MW micro wave NBSN-bromosuccinimide NMR nuclear magnetic resonance p para Pd/C palladiumon carbon iPr isopropyl nPr n-propyl Rf retention factor (TLC) TBAFtetra-N-butylammoniumfluoride tert tertiary TFA trifluoroacetic acid THFtetrahydrofuran TLC thin layer chromatography TOTUO-((Ethoxycarbonyl)cyanomethyleneamino)-N,N,N′,N′-tetramethyltetrafluoroborate

Additional compounds of formula I can be prepared accordingly.

The experimental procedures for preparing the examples mentioned aboveare described below:

Building Block synthesis according to process BB:

[4-(4-Trifluoromethyl-phenoxy)-phenyl]-methanol

To a solution of 2.0 g commercially available4-(4-Trifluoromethyl-phenoxy)-benzoic acid in 180 ml tetrahydrofuran 269mg lithium aluminum hydride were added at −20° C. portionwise. Thereaction temperature was maintained between −5° C. and −20° C. Aftercompletion of the addition the cooling bath was removed and the reactionmixture was allowed to warm to room temperature. The reaction mixturewas stirred at room temperature for two hours. Then the reaction mixturewas cooled again to −40° C. and 3 ml water were added. The cooling bathwas removed and the reaction mixture was allowed to warm to roomtemperature. The reaction mixture was stirred at room temperature forfour hours. Then the reaction mixture was dried over MgSO4. The solventwas removed in vacuo and the residue purified by flash chromatography onsilica gel with the eluents n-heptane:ethyl acetate=9:1=>2:1 to obtain600 mg [4-(4-Trifluoromethyl-phenoxy)-phenyl]-methanol.

C14H11F3O2 (268.24), Rf(n-heptane:ethyl acetate=1:1)=0.41.

1-Chloromethyl-4-(4-Trifluoromethyl-phenoxy)-benzene

5.37 g 1H-Benzotriazole were dissolved in 10.9 ml thionyl chloride. Thesolution was diluted with dichloromethane to a total volume of 100 ml toobtain a 1.5 M solution of thionylchloride and 1H-Benzotriazole. 600 mg[4-(4-Trifluoromethyl-phenoxy)-phenyl]-methanol were dissolved in 50 mldichloromethane. 1.86 ml of the above 1.5 M solution of thionylchlorideand 1H-Benzotriazole were added. The reaction mixture was stirred atroom temperature for three hours. The precipitate was filtered offthrough a pad of Na2SO4. The filtrate was evaporated in vacuo and theresidue purified by flash chromatography on silica gel with the eluentsn-heptane:ethyl acetate=1:2=>1:1 to obtain 613 mg1-Chloromethyl-4-(4-Trifluoromethyl-phenoxy)-benzene.

C14H10ClF3O (286.68), Rf(n-heptane:ethyl acetate=2:1)=0.67.

1-Chloromethyl-4-(2-methoxy-Phenoxy)-benzene

According to the method described for1-Chloromethyl-4-(4-Trifluoromethyl-phenoxy)-benzene1-Chloromethyl-4-(2-methoxy-phenoxy)-benzene was obtained fromcommercially available 4-(2-methoxyphenoxy)benzoic acid.

C14H13ClO2 (248.71), Rf(n-heptane:ethyl acetate=2:1)=0.54.

3-Chloromethyl-6-methoxy-benzofuran

According to the method described for1-Chloromethyl-4-(4-Trifluoromethyl-phenoxy)-benzene3-Chloromethyl-6-methoxy-benzofuran was obtained from commerciallyavailable 6-methoxy-benzofuran-3-carboxylic acid ethyl ester.

C10H9ClO2 (196.64), Rf(n-heptane:ethyl acetate=2:1)=0.59.

2-Chloromethyl-5-methoxy-benzofuran

According to the method described for1-Chloromethyl-4-(4-Trifluoromethyl-phenoxy)-benzene2-Chloromethyl-5-methoxy-benzofuran was obtained from commerciallyavailable 5-methoxy-benzofuran-2-carboxylic acid.

C10H9ClO2 (196.64), Rf(n-heptane:ethyl acetate=1:1)=0.74.

5-Chloromethyl-4-methyl-2-(3-trifluoromethyl-phenyl)-thiazole

According to the method described for1-Chloromethyl-4-(4-Trifluoromethyl-phenoxy)-benzene5-Chloromethyl-4-methyl-2-(3-trifluoromethyl-phenyl)-thiazole wasobtained from commercially available4-Methyl-2-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid.

C12H9ClF3NS (291.72), Rf(n-heptane:ethyl acetate=2:1)=0.52.

5-Chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole

According to the method described for1-Chloromethyl-4-(4-Trifluoromethyl-phenoxy)-benzene5-Chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole wasobtained from commercially available4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid.

C12H9ClF3NS (291.72), MS (ESI): 292.0 (M+H+), Rf(n-heptane:ethylacetate=2:1)=0.54.

The following examples were prepared according to process A:

EXAMPLE 1N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzenesulfonamide

4-Acetoxy-benzenesulfonic acid sodium salt

50.0 g p-Phenolsulfonic acid sodium salt mono hydrate were suspended in180 ml triethylamine. To this stirred suspension 72.3 ml acetic acidanhydride were added. The reaction temperature was maintained below 60°C. The reaction mixture was stirred at room temperature overnight. Thereaction mixture was evaporated in vacuo. The residue was coevaporatedwith 600 ml toluene twice. The residue was suspended in 600 ml ethylacetate and stirred at 80° C. The precipitate was filtered off warm undwashed with ethyl acetate then dried in vacuo to obtain 42.9 g4-Acetoxy-benzenesulfonic acid sodium salt as a white solid.

C8H7O5S.Na (238.20).

Acetic acid 4-chlorosulfonyl-phenyl ester

42.9 g 4-Acetoxy-benzenesulfonic acid sodium salt were suspended in 135ml thionyl chloride. Then 0.5 ml dimethylformamide were added. Thereaction mixture was heated under reflux for one hour. The cooledreaction mixture was evaporated in vacuo. The residue was coevaporatedwith 600 ml toluene twice. The residue was suspended in 500 mldichloromethane and stirred at room temperature for thirty minutes. Thesuspension was filtered and the filtrate reduced in vacuo to one fifthof its volume. To this stirred solution 400 ml n-heptane were addeddropwise and acetic acid 4-chlorosulfonyl-phenyl ester precipitated as awhite solid. The precipitate was filtered off and dried in vacuo toobtain 40.4 g acetic acid 4-chlorosulfonyl-phenyl ester.

C8H7ClO4S (234.66).

Acetic acid 4-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-phenyl ester

4.1 g acetic acid 4-chlorosulfonyl-phenyl ester were added to a stirredsolution of 2.5 g 5-isopropyl-[1,3,4]thiadiazol-2-ylamine in 35 mlpyridine. The reaction mixture was stirred at room temperatureovernight. The pyridine was removed in vacuo and the residue dissolvedin 200 ml dichloromethane and washed with 60 ml water. The organic layerwas dried over MgSO4. Then the solvent was removed in vacuo and theresulting residue purified by flash chromatography on silica gel withthe eluents n-heptane:ethyl acetate=1:1=>1:3 to obtain 4.47 g Aceticacid 4-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-phenyl esterimpurified with 40% of the byproductN-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-acetamide. The material was usedwithout further purification.

C13H15N3O4S2 (341.41), MS (ESI): 342.1 (M+H+).

Acetic acid4-[(5-isopropyl-[1,3,4]thiadiazol-2-yl)-(2-trimethylsilanyl-ethoxymethyl)-sulfamoyl]-phenylester

3.3 g Acetic acid 4-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-phenylester were dissolved in 12 ml dichloromethane. 2.69 mlN,N-diisopropylethylamine, 78 mg 4-dimethylaminopyridine and 2.1 g2-(trimethylsilyl)ethoxymethyl chloride were added. The reaction mixturewas stirred at room temperature for one hour. The solvent was removed invacuo and the residue purified by flash chromatography on silica gelwith the eluents n-heptane:ethyl acetate=1:1=>1:3 to obtain 2.7 g aceticacid4-[(5-isopropyl-[1,3,4]thiadiazol-2-yl)-(2-trimethylsilanyl-ethoxymethyl)-sulfamoyl]-phenylester.

C19H29N3O5S2Si (471.67), MS (ESI): 472.2 (M+H+), Rf(n-heptane:ethylacetate=1:1)=0.47.

4-Hydroxy-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-N-(2-trimethylsilanyl-ethoxymethyl)-benzenesulfonamide

2.7 g of4-[(5-isopropyl-[1,3,4]thiadiazol-2-yl)-(2-trimethylsilanyl-ethoxymethyl)-sulfamoyl]-phenylester were dissolved in 135 ml methanol. 637 mg sodium carbonate,dissolved in 3 ml water were added and the reaction mixture stirred atroom temperature for fifteen minutes. The solvent was removed in vacuoand the residue dissolved in 100 ml ethyl acetate and washed with 100 mlwater. The aqueous phase was extracted with 80 ml ethyl acetate. Thecombined organic layers were dried over MgSO4. The solvent was removedin vacuo to obtain 2.4 g4-Hydroxy-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-N-(2-trimethylsilanyl-ethoxymethyl)-benzenesulfonamide.

C17H27N3O4S2Si (429.64), Rf(n-heptane:ethyl acetate=1:1)=0.37.

N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-N-(2-trimethylsilanyl-ethoxymethyl)-benzenesulfonamide

360 mg of4-Hydroxy-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-N-(2-trimethylsilanylethoxymethyl)-benzenesulfonamidewere dissolved in 2 ml dimethylformamide. 527 mg cesium carbonate and asolution of 236 mg in 2 ml dimethylformamide were added. The reactionmixture was stirred at room temperature for two hours. Then the solventwas removed in vacuo and the residue purified by flash chromatography onsilica gel with the eluents n-heptane:ethyl acetate=4:1=>1:1 to obtain180 mgN-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-N-(2-trimethylsilanyl-ethoxymethyl)-benzenesulfonamide.

C29H35F3N4O4S3Si (684.90), MS (ESI): 685.2 (M+H+), Rf(n-heptane:ethylacetate=1:1)=0.48.

N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzenesulfonamide

160 mg ofN-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-4-[4-methyl-2-(4-trifluoromethylphenyl)-thiazol-5-ylmethoxy]-N-(2-trimethylsilanyl-ethoxymethyl)-benzenesulfonamidewere dissolved in 3.8 ml tetrahydrofuran. 977 mgtetra-N-butylammoniumfluoride were added and the reaction mixture wasstirred at room temperature for two hours and at 40° C. for twentyminutes. The solvent was removed in vacuo and the residue purified byRP-HPLC to obtain 32 mgN-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzenesulfonamideas amorphous solid.

C23H21F3N4O3S3 (554.64), MS (ESI): 555.0 (M+H+).

EXAMPLE 2N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[4-methyl-2-(3-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzenesulfonamide

According to the method described in example1N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[4-methyl-2-(3-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzenesulfonamidewas obtained from4-Hydroxy-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-N-(2-trimethylsilanyl-ethoxymethyl)-benzenesulfonamideand 5-Chloromethyl-4-methyl-2-(3-trifluoromethyl-phenyl)-thiazole.

C23H21F3N4O3S3 (554.64), MS (ESI): 555.1 (M+H+).

EXAMPLE 3N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-(6-methoxy-benzofuran-3-ylmethoxy)-benzenesulfonamide

According to the method described in example1N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-(6-methoxy-benzofuran-3-ylmethoxy)-benzenesulfonamidewas obtained from4-Hydroxy-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-N-(2-trimethylsilanyl-ethoxymethyl)-benzenesulfonamideand 3-Chloromethyl-6-methoxy-benzofuran.

C21H21N3O5S2 (459.55), MS (ESI): 460.2 (M+H+).

EXAMPLE 4N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[4-(4-trifluoromethyl-phenoxy)-benzyloxy]-benzenesulfonamide

According to the method described in example1N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[4-(4-trifluoromethyl-phenoxy)-benzyloxy]-benzenesulfonamidewas obtained from4-Hydroxy-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-N-(2-trimethylsilanyl-ethoxymethyl)-benzenesulfonamideand 1-Chloromethyl-4-(4-Trifluoromethyl-phenoxy)-benzene.

C25H22F3N3O4S2 (549.59), MS (ESI): 550.2 (M+H+).

EXAMPLE 5N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-4-[4-(2-methoxy-phenoxy)-benzyloxy]-benzenesulfonamide

According to the method described in example1N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[4-(2-methoxy-phenoxy)-benzyloxy]-benzenesulfonamidewas obtained from4-Hydroxy-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-N-(2-trimethylsilanyl-ethoxymethyl)-benzenesulfonamideand 1-Chloromethyl-4-(2-methoxy-phenoxy)-benzene.

C25H25N3O5S2 (511.62), MS (ESI): 512.2 (M+H+).

EXAMPLE 64-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-benzenesulfonamide

According to the method described in example14-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-benzenesulfonamidewas obtained from4-Hydroxy-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-N-(2-trimethylsilanyl-ethoxymethyl)-benzenesulfonamideand 4-Butyl-5-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole¹. ¹EP04007879

C26H27F3N4O3S3 (596.72), MS (ESI): 597.2 (M+H+).

EXAMPLE 7N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[5-methyl-2-(4-phenoxy-Phenyl)-oxazol-4-ylmethoxy]-benzenesulfonamide

According to the method described in example1N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[5-methyl-2-(4-phenoxy-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonamidewas obtained from4-Hydroxy-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-N-(2-trimethylsilanyl-ethoxymethyl)-benzenesulfonamideand 4-Iodomethyl-5-methyl-2-(4-phenoxy-phenyl)-oxazole². ² WO 2004075815

C28H26N4O5S2 (562.67), MS (ESI): 563.2 (M+H+).

EXAMPLE 84-(2-Cyclohexyl-oxazol-4-ylmethoxy)-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-benzenesulfonamide

According to the method described in example 14-(2-Cyclohexyl-oxazol-4-ylmethoxy)-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-benzenesulfonamidewas obtained from4-Hydroxy-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-N-(2-trimethylsilanyl-ethoxymethyl)-benzenesulfonamideand 2-Cyclohexyl-4-iodomethyl-oxazole³. ³ WO 2004075815

C21H26N4O4S2 (462.59), MS (ESI): 463.1 (M+H+).

EXAMPLE 9N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[5-(4-methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethoxy]-benzenesulfonamide

According to the method described in example1N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[5-(4-methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethoxy]-benzenesulfonamidewas obtained from4-Hydroxy-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-N-(2-trimethylsilanyl-ethoxymethyl)-benzenesulfonamideand commercially available3-Chloromethyl-5-(4-methoxy-phenyl)-[1,2,4]oxadiazole.

C21H21N5O5S2 (487.56), MS (ESI): 488.2 (M+H+).

EXAMPLE 10N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzenesulfonamide

According to the method described in example1N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzenesulfonamidewas obtained from4-Hydroxy-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-N-(2-trimethylsilanyl-ethoxymethyl)-benzenesulfonamideand 4-Iodomethyl-2-(4-methoxy-phenyl)-5-methyl-oxazole⁴. ⁴ WO2004076428, WO 2004076427, WO 2004076426, US 2004122069, WO 2003020269

C23H24N4O5S2 (500.60), MS (ESI): 501.1 (M+H+).

EXAMPLE 114-(2-Biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-benzenesulfonamide

According to the method described in example 14-(2-Biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-benzenesulfonamidewas obtained from4-Hydroxy-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-N-(2-trimethylsilanyl-ethoxymethyl)-benzenesulfonamideand 2-Biphenyl-4-yl-4-iodomethyl-5-methyl-oxazole⁵. ⁵ WO 2004076428, WO2004076427

C28H26N4O4S2 (546.67), MS (ESI): 547.2 (M+H+).

EXAMPLE 12N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-(5-methoxy-benzofuran-2-ylmethoxy)-benzenesulfonamide

According to the method described in example1N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-(5-methoxy-benzofuran-2-ylmethoxy)-benzenesulfonamidewas obtained from4-Hydroxy-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-N-(2-trimethylsilanyl-ethoxymethyl)-benzenesulfonamideand 2-Chloromethyl-5-methoxy-benzofuran.

C21H21N3O5S2 (459.55), MS (ESI): 460.1 (M+H+).

The following examples were prepared according to process B:

EXAMPLE 13N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[2-(4-methoxy-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonamide

2-(4-Methoxy-phenyl)-4-phenoxymethyl-oxazole

373 mg phenol were dissolved in 10 ml tetrahydrofuran. 92 mg sodiumhydride were added and the reaction mixture was stirred at roomtemperature for twenty minutes 1.0 g4-Iodomethyl-2-(4-methoxy-phenyl)-oxazole⁶ were added at −10° C. Thereaction mixture was stirred at room temperature for six hours. Thereaction mixture was poured on 100 ml water and extracted twice withportions of 120 ml dichloromethane. The combined organic layers weredried over MgSO4. The solvent was then removed in vacuo to obtain 950 mg2-(4-Methoxy-phenyl)-4-phenoxymethyl-oxazole. ⁶ US 2004122069, WO2003020269

C17H15NO3 (281.31), MS (ESI): 282.2 (M+H+).

4-[2-(4-Methoxy-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl chloride

950 mg 2-(4-Methoxy-phenyl)-4-phenoxymethyl-oxazole were dissolved in 9ml dichloromethane. At −20° C. 0.90 ml chlorosulfonic acid were addeddropwise. The cooling bath was removed and the reaction mixture stirredat room temperature for two hours. The reaction mixture was cooled to 0°C., then 20 ml ice water were added and the reaction mixture extractedfive times with portions of 50 ml dichloromethane. The combined organiclayers were washed with water and then dried over MgSO4. The solvent wasthen removed in vacuo to obtain 580 mg4-[2-(4-Methoxy-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl chloride.

C17H14ClNO5S (379.82), MS (ESI): 380.1 (M+H+).

N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[2-(4-methoxy-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonamide

580 mg 4-[2-(4-Methoxy-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonylchloride were added to a stirred solution of 275 mg5-isopropyl-[1,3,4]thiadiazol-2-ylamine in 35 ml pyridine. 18 mg4-Dimethylaminopyridine were added. The reaction mixture was stirred atroom temperature overnight. The pyridine was removed in vacuo and theresidue coevaporated with 15 ml toluene. The residue was purified byRP-HPLC to obtain 19 mgN-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[2-(4-methoxy-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonamide.

C22H22N4O5S2 (486.57), MS (ESI): 487.1 (M+H+).

EXAMPLE 144-[5-Ethyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-benzenesulfonamide

According to the method described in example134-[5-Ethyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-benzenesulfonamidewas obtained from phenol, 5-isopropyl-[1,3,4]thiadiazol-2-ylamine and5-Ethyl-4-iodomethyl-2-(3-trifluoromethyl-phenyl)-oxazole⁷. ⁷ WO2004076427, WO 2004076426

C24H23F3N4O4S2 (552.60), MS (ESI): 553.2 (M+H+).

EXAMPLE 15N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[5-methyl-2-(4-trifluoromethoxy-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonamide

According to the method described in example 13N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[5-methyl-2-(4-trifluoromethoxy-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonamidewas obtained from phenol, 5-isopropyl-[1,3,4]thiadiazol-2-ylamine and4-Iodomethyl-5-methyl-2-(4-trifluoromethoxy-phenyl)-oxazole⁸. ⁸ WO2004076428

C23H21F3N4O5S2 (554.57), MS (ESI): 555.1 (M+H+).

EXAMPLE 16N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[5-isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonamide

According to the method described in example 13N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-[5-isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonamidewas obtained from phenol, 5-isopropyl-[1,3,4]thiadiazol-2-ylamine and4-Iodomethyl-5-isopropyl-2-(4-trifluoromethyl-phenyl)-oxazole⁹. ⁹ WO2004076426

C25H25F3N4O4S2 (566.63), MS (ESI): 567.2 (M+H+).

EXAMPLE 174-[5-Ethyl-2-(2-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-benzenesulfonamide

According to the method described in example134-[5-Ethyl-2-(2-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-benzenesulfonamidewas obtained from phenol, 5-isopropyl-[1,3,4]thiadiazol-2-ylamine and5-Ethyl-4-iodomethyl-2-(2-trifluoromethyl-phenyl)-oxazole ¹⁰. ¹⁰ WO2004076447, WO 2004076428

C24H23F3N4O4S2 (552.60), MS (ESI): 553.1 (M+H+).

EXAMPLE 184-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-N-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-benzenesulfonamide

5-Methyl-4-(2-phenoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-thiazole

400 mg 2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethanol¹¹,164 mg phenol and 438 mg triphenylphosphine were dissolved in 10 mldichloromethane. To this ice cooled reaction mixture 291 mgdiethyldiazodicarboxylate were added. The cooling bath was removed andthe reaction mixture stirred at room temperature for one hour. Thesolvent was removed in vacuo and the residue purified by chromatographyon silica gel with the eluents n-heptane:ethyl acetate=9:1 to obtain 306mg 5-Methyl-4-(2-phenoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-thiazole.¹¹ WO 2005051945, WO 2003059895, WO 2002100403, WO 2002092084, WO2000008002, WO 9203425

C19H16F3NOS (363.40), MS (ESI): 364.1 (M+H+), Rf(n-heptane:ethylacetate=2:1)=0.52.

4-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-N-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-benzenesulfonamide

According to the method described in example134-{2-[5-Methyl-2-(4-trifluoromethylphenyl)-thiazol-4-yl]-ethoxy}-N-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-benzenesulfonamidewas obtained from5-Methyl-4-(2-phenoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-thiazole and5-trifluoromethyl-[1,3,4]thiadiazol-2-ylamine.

C22H16F6N4O3S3 (594.58), MS (ESI): 595.0 (M+H+).

EXAMPLE 19N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy}-benzenesulfonamide

According to the method described in example 13 and 18N-(5-Isopropyl-[1,3,4]thiadiazol-2-yl)-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy}-benzenesulfonamidewas obtained from phenol, 5-isopropyl-[1,3,4]thiadiazol-2-ylamine and2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethanol¹². ¹² WO2005051945, WO 2003059895, WO 2002100403, WO 2002092084, WO 2000008002,WO 9203425

C24H23F3N4O4S2 (552.60), MS (ESI): 553.1 (M+H+).

1. A compound of formula I:

wherein R1 is selected from the group consisting of (C1-C6) alkyl,(C0-C6) alkylene-(C3-C6) cycloalkyl, (C0-C6) alkylene-O-(C1-C6) alkyl,(C0-C6) alkylene-O-(C3-C6) cycloalkyl, (C0-C6) alkylene-(C6-C14) aryl,and (C0-C6) alkylene-(C5-C15) heteroaryl, wherein alkyl, alkylene, aryland cycloalkyl are unsubstituted or mono-, di- or tri-substituted by F,Cl, Br, (C1-C6) alkyl, O-(C1-C6) alkyl, CF₃, OCF₃, CN, CO-(C1-C6) alkyl,COO-(C1-C6) alkyl, CON((C0-C6) alkylene-H) (C0-C6) alkylene-H), andS(O)_(m)(C1-C6) alkyl; R2 and R3 are independently selected from thegroup consisting of H, halogen, (C1-C6) alkyl, (C0-C4)alkylene-O-(C0-C4) alkylene-H, SCH3 and CN, wherein alkyl and alkyleneis unsubstituted or mono-, di- or trisubstituted by F; R4, R5, R6 and R7are independently selected from the group consisting of H, (C1-C6)alkyl, (C0-C4) alkylene-(C3-C6) cycloalkyl, (C0-C6) alkylene-(C6-C14)aryl, (C0-C6) alkylene-(C5-C15) heteroaryl, (C0-C6) alkylene-(C3-C15)heterocycloalkyl and (C0-C6) alkylene-(C3-C15) heterocycloalkenyl,wherein alkyl, cycloalkyl, aryl, heterocycloalkyl, heterocycloalkenyland heteroaryl are unsubstituted or mono-, di- or trisubstituted by F,Cl, Br, CF3, (C1-C4) alkyl and (C0-C4)-alkylene-O-(C0-C4) alkylene-H; mis 0 or 1; A is (C6-C14) aryl or (C5-C15) heteroaryl; B is selected fromthe group consisting of (C6-C14) aryl, (C3-C12) cycloalkyl, and (C5-C15)heteroaryl; Z is a bond, O or Ring A and Ring B together form anannealed (C5-C15) heterocyclic or (C8-C14) aromatic ring system; and Zis absent; R8 and R9 are independently selected from the groupconsisting of H, halogen, (C1-C6) alkyl, (C0-C4) alkylene-O-(C0-C4)alkylene-H, SCF3, SF5, S(O)2CF3, O—(C6-C14) aryl, (C6-C14) aryl, andNO2, wherein alkyl and alkylene is unsubstituted or mono, bi- ortri-substituted by F and wherein aryl is unsubstituted or mono-, di- ortri-substituted by F, Cl, Br, CF3, (C1-C4) alkyl and(C0-C4)-alkylene-O-(C0-C4) alkylene-H; p is 0, 1, 2 or 3; q is 0, 1 or2; its' stereoisomers, enantiomers, tautomers their salts and mixturesthereof.
 2. The compounds of the formula I as recited in claim 1,wherein R1 is selected from the group consisting of (C1-C6) alkyl,(C0-C6) alkylene-O-(C1-C6) alkyl and (C0-C6) alkylene-(C6-C14) aryl,wherein alkyl, alkylene and aryl are unsubstituted or mono- ordisubstituted by F; R2 and R3 are independently selected from the groupconsisting of H, halogen, (C1-C6) alkyl, (C0-C4) alkylene-O-(C0-C4)alkylene-H, wherein alkyl and alkylene is unsubstituted or mono-, di- ortrisubstituted by F; 0ne of R4, R5, R6 and R7 is selected from the groupconsisting of H, (C1-C6) alkyl, (C0-C2) alkylene-(C3-C6) cycloalkyl,(C0-C2) alkylene-(C6-C10) aryl, (C0-C2) alkylene-(C5-C10) heteroaryl,(C0-C2) alkylene-(C3-C10) heterocycloalkyl, and (C0-C2)alkylene-(C3-C10) heterocycloalkenyl, wherein alkyl, cycloalkyl, aryl,heterocycloalkyl, heterocycloalkenyl and heteroaryl are unsubstituted ormono-, di- or trisubstituted by F, Cl, CF3, (C1-C4) alkyl and(C0-C4)-alkylene-O-(C0-C4) alkylene-H; and the other three of thesubstituents is H m is 0 or 1; A is (C6-C10) aryl, (C5-C10) heteroaryl;B is selected from the group consisting of (C6-C10) aryl, (C6-C8)cycloalkyl, (C5-C10) heteroaryl; Z is a bond or O; A and B together forman annealed (C8-C10) heterocyclic ring and Z is absent; R8 is H or(C1-C6) alkyl; R9 is H, (C1-C6) alkyl, (C0-C4) alkylene-O-(C0-C4)alkylene-H, O-(C6-C10) aryl, wherein alkyl and alkylene is unsubstitutedor mono, bi- or trisubstituted by F; p is 0, 1, 2; q is 0,
 1. 3. Thecompound of formula I as claimed in claim 1, wherein R1 is selected fromthe group consisting of (C1-C6) alkyl, phenyl, and (C3-C6) cycloalkyl.4. The compounds of formula I as recited in claim 2, wherein R1 isisopropyl.
 5. The compounds of formula I as recited in claim 4, whereinR2 and, R3 are H.
 6. The compounds of formula I as recited in claim 5,wherein R4, R5, R6 and R7 are H.
 7. The compounds of formula I asrecited in claim 6, wherein m is
 0. 8. The compounds of formula I asrecited in claim 7, wherein A is selected from the group consisting ofoxazole, thiazole, phenyl and, 1,2,4-oxadiazole.
 9. The compounds offormula I as recited in claim 8 wherein B is phenyl or cyclohexyl. 10.The compounds of formula I as recited in claim 9, wherein z is a bond.11. The compounds of formula I as recited in claim 9, wherein A and Btogether form a benzofuran ring and z is absent.
 12. The compounds ofthe formula I as recited in claim 10, wherein R8 is H, (C1-C4) alkyl andp is 0 or
 1. 13. The compounds of the formula I as recited in claim 11,wherein R9 is H, CF3, O-(C1-C4) alkyl, phenoxy and q is
 1. 14. Apharmaceutical composition comprising one or more compounds of theformula I as recited in claim
 1. 15. A process for preparing apharmaceutical composition comprising one or more of the compounds asclaimed in claim 1, which comprises mixing the active compound with apharmaceutically suitable carrier and bringing this mixture into a formsuitable for administration.